Thèses : « Fibrosi renale »

1

Bedino, Giulia <1980&gt. « La terapia combinata di cellule mesenchimali stromali e aceinibitori riduce la fibrosi renale in un modello animale di ostruzione ureterale unilaterale ». Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6297/1/bedino_giulia_tesi.pdf.

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Le cellule mesenchimali stromali (MSC) sono cellule multipotenti e numerosi studi hanno mostrato i loro effetti benefici nel danno renale acuto ma non sono ancora stati dimostrati potenziali effetti nella malattia renale cronica. L'ostruzione ureterale unilaterale (UUO) è un modello di fibrosi interstiziale nel quale l'attivazione di molecole vasoattive, citochine profibrotiche e infiammatorie gioca un ruolo patogenetico nello sviluppo dell'apoptosi e atrofia tubulare. Il sistema renina-angiotensina (RAS) gioca un ruolo chiave nello sviluppo della fibrosi renale e i farmaci che hanno come target l'angiotensina II, principale mediatore del RAS, sono attualmente la terapia più efficace nel ridurre la progressione della malattia renale cronica. E' noto che gli ACE-inibitori (ACEi) inducono un aumento compensatorio della renina plasmatica per la mancaza del feedback negativo sulla sua produzione. Tuttavia, la renina (R) promuove il danno renale non solo stimolando la produzione di ANGII, ma anche up-regolando geni profibrotici attraverso l'attivazione del recettore renina/prorenina. Lo scopo dello studio è stato indagare se l'infusione di MSC riduceva il danno renalein un modello animale di UUO e comparare gli eventuali effetti protettivi di ACEi e MSC in UUO. Abbiamo studiato 5 gruppi di ratti. A: sham operati. B: ratti sottoposti a UUO che ricevevano soluzione salina. C: ratti sottoposti a UUO che ricevavano MSC 3X106 nella vena della coda al giorno 0. D:ratti sottoposti a UUO che ricevevano lisinopril dal g 1 al g 21. E: ratti sottoposti a UUO che ricevevano MSC 3X106 nella vena della coda al giorno 0 e lisinopril dal g 1 al g 21. I ratti sono stati sacrificati al giorno 7 e 21. I risultati dello studio mostrano che MSC in UUO prevengono l'aumento della renina, riducono la generazione di ANGII e che in terapia combinata con ACEi riducono ulteriormente l'ANGII, determinando una sinergia nel miglioramento della fibrosi renale.
Mesenchymal stromal cells (MSC) are multipotent cells with immunomodulant and anti-inflammatory effect. Several studies have shown MSC beneficial effect in acute kidney injury but are not yet known MSC effects in chronic kidney disease. Unilateral ureteral obstruction (UUO) is a model of renal interstitial fibrosis, the final common pathway for progressive renal diseases where the activation of vasoactive molecules, inflammatory and profibrotic cytokines plays a pathogenetic role in the development of cell apoptosis and tubular atrophy. Renin-angiotensin system (RAS) plays a pivotal role in renal fibrosis and agents that target angiotensin II, principal mediator of RAS, are the most effective therapy to reduce progression of chronic kidney disease. Its known that angiotensin-converting enzyme inhibitors (ACEi) induce a compensatory increase in plasma renin levels because of the disruption of the negative feedback of its production. However renin (R) promotes renal injury not only by stimulating angiotensin II (ANG II) generation, but also up-regulating pro-fibrotic genes through renin/prorenin receptor activation. The aim of the study was to investigate whether MSC infusion attenuate renal injury in a rat model of UUO and to compare the protective effects of ACEi and MSC in UUO. We studied 5 groups of rats. A: rats sham operated. B: rats UUO received saline solution on day 0 (vehicle control). C: rats UUO received MSC 3X106 on day 0 via tail vein. D: rats UUO received lisinopril from d 1 to 21. E: rats UUO received MSC on d 0, and lisinopril from d 1 to 21. Rats were sacrified on d 7 and 21. Our results show that MSC in UUO rat model prevent renin increase, reduce angiotensin II generation and in combination therapy with ACEi suppress further angiotensin II block, thereby lead to a synergy in ameliorating renal fibrosis.

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2

Bedino, Giulia <1980&gt. « La terapia combinata di cellule mesenchimali stromali e aceinibitori riduce la fibrosi renale in un modello animale di ostruzione ureterale unilaterale ». Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6297/.

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Le cellule mesenchimali stromali (MSC) sono cellule multipotenti e numerosi studi hanno mostrato i loro effetti benefici nel danno renale acuto ma non sono ancora stati dimostrati potenziali effetti nella malattia renale cronica. L'ostruzione ureterale unilaterale (UUO) è un modello di fibrosi interstiziale nel quale l'attivazione di molecole vasoattive, citochine profibrotiche e infiammatorie gioca un ruolo patogenetico nello sviluppo dell'apoptosi e atrofia tubulare. Il sistema renina-angiotensina (RAS) gioca un ruolo chiave nello sviluppo della fibrosi renale e i farmaci che hanno come target l'angiotensina II, principale mediatore del RAS, sono attualmente la terapia più efficace nel ridurre la progressione della malattia renale cronica. E' noto che gli ACE-inibitori (ACEi) inducono un aumento compensatorio della renina plasmatica per la mancaza del feedback negativo sulla sua produzione. Tuttavia, la renina (R) promuove il danno renale non solo stimolando la produzione di ANGII, ma anche up-regolando geni profibrotici attraverso l'attivazione del recettore renina/prorenina. Lo scopo dello studio è stato indagare se l'infusione di MSC riduceva il danno renalein un modello animale di UUO e comparare gli eventuali effetti protettivi di ACEi e MSC in UUO. Abbiamo studiato 5 gruppi di ratti. A: sham operati. B: ratti sottoposti a UUO che ricevevano soluzione salina. C: ratti sottoposti a UUO che ricevavano MSC 3X106 nella vena della coda al giorno 0. D:ratti sottoposti a UUO che ricevevano lisinopril dal g 1 al g 21. E: ratti sottoposti a UUO che ricevevano MSC 3X106 nella vena della coda al giorno 0 e lisinopril dal g 1 al g 21. I ratti sono stati sacrificati al giorno 7 e 21. I risultati dello studio mostrano che MSC in UUO prevengono l'aumento della renina, riducono la generazione di ANGII e che in terapia combinata con ACEi riducono ulteriormente l'ANGII, determinando una sinergia nel miglioramento della fibrosi renale.
Mesenchymal stromal cells (MSC) are multipotent cells with immunomodulant and anti-inflammatory effect. Several studies have shown MSC beneficial effect in acute kidney injury but are not yet known MSC effects in chronic kidney disease. Unilateral ureteral obstruction (UUO) is a model of renal interstitial fibrosis, the final common pathway for progressive renal diseases where the activation of vasoactive molecules, inflammatory and profibrotic cytokines plays a pathogenetic role in the development of cell apoptosis and tubular atrophy. Renin-angiotensin system (RAS) plays a pivotal role in renal fibrosis and agents that target angiotensin II, principal mediator of RAS, are the most effective therapy to reduce progression of chronic kidney disease. Its known that angiotensin-converting enzyme inhibitors (ACEi) induce a compensatory increase in plasma renin levels because of the disruption of the negative feedback of its production. However renin (R) promotes renal injury not only by stimulating angiotensin II (ANG II) generation, but also up-regulating pro-fibrotic genes through renin/prorenin receptor activation. The aim of the study was to investigate whether MSC infusion attenuate renal injury in a rat model of UUO and to compare the protective effects of ACEi and MSC in UUO. We studied 5 groups of rats. A: rats sham operated. B: rats UUO received saline solution on day 0 (vehicle control). C: rats UUO received MSC 3X106 on day 0 via tail vein. D: rats UUO received lisinopril from d 1 to 21. E: rats UUO received MSC on d 0, and lisinopril from d 1 to 21. Rats were sacrified on d 7 and 21. Our results show that MSC in UUO rat model prevent renin increase, reduce angiotensin II generation and in combination therapy with ACEi suppress further angiotensin II block, thereby lead to a synergy in ameliorating renal fibrosis.

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3

Mezzalira, Giorgia. « Studio delle patologie renali del cane ». Doctoral thesis, Università degli studi di Padova, 2009. http://hdl.handle.net/11577/3425666.

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This study selected 40 canine patients with signalement, anamnesis, lab exams and renal biopsy or renal sample taken during necropsy. Renal sections stained with H&E, PAS, PASM, Masson's Thrichrome and AFOG was evaluated by three independent pathologists. Later, morphological diagnoses were correlated with lab exams.
Questo studio ha selezionato 40 cani completi di segnalamento, anamnesi, esami di laboratorio e campione bioptico renale prelevato tramite biopsia o post mortem, in sede necroscopica. Le sezioni istologiche ottenute e colorate con ematossilina ed eosina, PAS, PASM, Tricromica di Masson ed AFOG sono state valutate da tre patologi in sede separata. Le diagnosi morfologiche sono state poste poi in relazione con i dati laboratoristici in possesso.

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CORRADI, BARBARA. « Ruolo di N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (Ac-SDKP) nella progressione della Nefropatia Diabetica ». Doctoral thesis, Università degli Studi di Milano-Bicocca, 2013. http://hdl.handle.net/10281/43715.

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La nefropatia diabetica è la principale causa di insufficienza renale terminale. N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (Ac-SDKP), tetrapeptide fisiologicamente presente nel plasma e nei tessuti, viene idrolizzato dall’ enzima di conversione dell’angiotensina. Il tetrapeptide ha un effetto antifibrotico sul sistema cardiovascolare e nel rene in modelli sperimentali di ipertensione, infarto del miocardio e nefropatie. Lo scopo del nostro lavoro è stato studiare gli effetti antifibrotici di Ac-SDKP in un modello sperimentale di nefropatia diabetica, e il potenziale effetto additivo del tetrapeptide, in aggiunta al singolo trattamento con ACE-inibitore, sulla progressione della fibrosi renale. A 28 ratti Sprague Dawley e’ stato indotto diabete con un’iniezione di streptozotocina, mentre a 10 ratti controllo e’ stata somministrata solo soluzione tampone. Dopo l’ insorgenza di diabete a 11 ratti è stato somministrato un inibitore dell’enzima di conversione dell’angiotensina (ACE-inibitore, ramipril 3 mg/Kg/die). Dopo 2 mesi di trattamento con ACE-inibitore a 7 ratti diabetici e a 6 ratti diabetici trattati con ramipril è stato somministrato per 8 settimane Ac-SDKP, alla dose di 1 mg/Kg/die, attraverso minipompe osmotiche impiantate nella regione infrascapolare. A 10 ratti controllo, a 10 ratti diabetici e a 5 ratti diabetici trattati con ramipril la minipompa osmotica rilasciava, per lo stesso periodo, solo soluzione fisiologica. Al termine del trattamento i ratti diabetici rispetto ai ratti del gruppo di controllo mostravano un significativo aumento del livello di glucosio, dell’ escrezione urinaria di albumina, della fibrosi renale e una significativa riduzione dell’espressione di nefrina a livello dei glomeruli. La somministrazione di Ac-SDKP riduceva significativamente la fibrosi renale nei ratti diabetici, ma non modificava significativamente l’escrezione urinaria di albumina. Il trattamento farmacologico con ACE-inibitore causava una significativa diminuzione dell’albuminuria e della fibrosi renale, ripristinando l’espressione della nefrina glomerulare. La somministrazione di Ac-SDKP, in aggiunta al trattamento con ACE-inibitore, riduceva ulteriormente la fibrosi renale rispetto al solo trattamento con ramipril, mentre non incrementava l’effetto antiproteinurico dell’ACE-inibitore. In conclusione questo studio ha dimostrato che la somministrazione di Ac-SDKP in un modello di nefropatia diabetica riduce la fibrosi renale. Il trattamento combinato (Ac-SDKP + ACE-inibitore) aumenta l’effetto antifibrotico dell’ACE-inibitore nel tessuto renale, suggerendo il benefico effetto di questa associazione farmacologica nel trattamento della nefropatia diabetica.

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Yi, Hao. « The Effect of Metformin on Inflammatory and Fibrotic Responses in Renal Fibrosis ». Thesis, The University of Sydney, 2019. https://hdl.handle.net/2123/21855.

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Chronic kidney disease (CKD) is a worldwide public health problem, with adverse outcomes of kidney failure, cardiovascular disease, and premature death. It is well recognised that renal fibrosis is the unifying pathology in almost all forms of progressive CKD. To date, kidney transplantation and dialysis are the only options for the management of end-stage kidney disease, which results in a significant burden on the health system. Hence innovative strategies are needed to both prevent and treat CKD. It is well recognised that inflammatory pathways play a central role in the progression of CKD and TGFβ-1 is a profibrotic cytokine found in CKD regardless of aetiology, which initiates and modulates a variety of pathophysiological processes. In renal disease, TGFβ-1 is upregulated and induces renal cells to produce extracellular matrix proteins leading to glomerulosclerosis as well as tubulointerstitial fibrosis. Different types of renal cells undergo different pathophysiological changes induced by TGF-β1, leading to apoptosis, hypertrophy and abnormalities of podocyte foot processes, which ultimately result in renal dysfunction. Regardless of the cause of CKD, multiple cytokines, growth factors, pro-inflammatory and fibrotic signalling pathways participate in the development of the pathological process in the kidney. Excessive deposition of extracellular matrix (ECM) is the most striking and common feature of renal fibrosis. Hence, targeting inflammatory and fibrotic responses, and ECM deposition, holds promise to limit fibrosis. Metformin, a biguanide, is a widely used drug in the treatment of type 2 diabetes mellitus (T2DM). It has been well-reviewed that metformin plays an important role in limiting cardiac and vascular fibrosis. Increasing evidence studies indicates metformin may be protective in renal fibrosis. However, the exact mechanisms of protection in renal injury are not fully understood or experimentally investigated. Thus, I initially examined the effect of metformin in TGFβ-1 induced fibrosis in human proximal tubular cells line (HK2 cells). Therefore, I further examined the effect of metformin on renal fibrosis in two mouse models of acute kidney injury (AKI; Folic Acid model (FA)) and chronic kidney injury (CKI, Adenine model). The studies have shown that metformin inhibited monocyte chemoattractant protein-1 (MCP-1) expression and TGFβ-1 signalling pathways in kidney proximal tubular cells exposed to TGFβ-1 by reducing mRNA, protein levels or phosphorylation of signalling molecules of non-Smad and Smad signalling pathways. Metformin also inhibited TGFβ-1 induced extracellular matrix deposition by reducing the expression of fibronectin and collagen IV in kidney proximal tubular cells exposed to TGF-β1. In animal studies, the acute phase of renal fibrosis was successfully established by giving folic acid via intraperitoneal injection, and then the antifibrotic effect of metformin was assessed by administering animals metformin or control for 14 days. The acute renal fibrosis mice model was successfully established by given adenine via gavage, and then treated with or without metformin for 14 days. The in vivo data has shown that folic acid induced impairment of renal function and the overexpression of fibronectin and collagen IV and inflammatory molecular MCP-1, F4/80 and intercellular adhesion molecule-1 (ICAM1) in kidneys compared to control groups; and the impaired renal function and inflammatory and fibrotic response were at least partially attenuated by metformin treatment. The chronic renal fibrosis mice model was successfully established by giving adenine through gavage daily and treatment with or without metformin for 21 days. The data showed that adenine induced renal dysfunction and the overexpression of fibronectin and collagen IV and inflammatory molecular MCP-1, F4/80 and ICAM in kidneys compared to control groups. Renal dysfunction and the inflammatory and fibrotic responses were reversed by metformin treatment. Collectively, these results suggest that metformin may have potential therapeutic value for the treatment of renal fibrosis independent of the cause of CKD.

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DaSilva, Santos Iara Karlla. « Impacto de la inflamación y fibrosis en la función del injerto renal ». Doctoral thesis, Universitat Autònoma de Barcelona, 2018. http://hdl.handle.net/10803/666855.

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A pesar de los grandes avances en el campo del trasplante renal (TR), los resultados a largo plazo aún no son óptimos. Varios estudios han demostrado que diversos factores como la inflamación precoz y/o la presencia de fibrosis intersticial (FI) están asociados a un peor pronóstico del injerto, pero todavía se trata de un tema controvertido. En este estudio analizamos el estado inflamatorio (Banff, macrófagos CD68+, fenotipos de macrófagos M1-M2) y la expresión génica de múltiples factores relacionados con la inflamación y FI (TGF-β1, metaloproteinasas, proteínas de matriz extracelular, entre otros) en injertos procedentes de donantes cadáver (DC) y los comparamos con un grupo control de donantes vivos (DV). Así mismo analizamos la potencial asociación de estos factores, ya desde antes de la implantación, con diversas variables clínicas y con la función renal a medio-largo plazo. Entre otros hallazgos, confirmamos que los órganos procedentes de DC presentan un mayor infiltrado intersticial de macrófagos CD68+ y describimos que tanto la expresión génica de varias proteínas pro-inflamatorias como pro-fibróticas se encuentran significativamente incrementadas en los DC incluso antes de la implantación. También observamos un aumento en la expresión génica de proteínas que promueven la infiltración leucocitaria, especialmente macrófagos, en el tejido (MCP-1, ICAM-1), así como de mediadores de inflamación como TNFα, IL1β. También se observó un aumento en la expresión génica de receptores de membrana de los macrófagos que les confiere el fenotipo inflamatorio (M1) así como el antinflamatorio (M2). En los DC también se observó un aumento significativo de los precursores y mediadores de FI. Es de destacar que muchos de estos parámetros (inflamatorios y pro-fibróticos) se asociaron a la función renal estimada (MDRD) en distintos tiempos de seguimiento. El análisis multivariante (regresión lineal múltiple) mostró que tanto la función retrasada del injerto como la expresión génica de TGF-β1 a los cuatro meses fueron predictores independientes de la función del injerto del último control (media 5.8 1.0 años). En conclusión, confirmamos la estrecha interconexión entre inflamación y fibrosis especialmente en el TR de DC, que ésta se inicia ya antes de la implantación y persiste post-TR y que estos factores muy precoces (potencialmente tratables) pueden determinar el pronóstico del injerto a largo plazo.
Despite great achievements in the field of renal transplantation (RT), long-term results are still not optimal. Several studies have shown that various factors such as early inflammation and/or the presence of interstitial fibrosis (IF) are associated with a worse graft prognosis, but this issue is still controversial and far from being resolved. In this study, we analyzed the inflammatory state (Banff, CD68 + macrophages, M1-M2 phenotypes, among others) and the gene expression of multiple factors related to both inflammation and IF (TGF-β1, metalloproteinases, extracellular matrix proteins, among others) in grafts from cadaveric donors (CD) and they were compared with a control group from living donors (LD). We also analyzed the potential association of all these factors with several clinical variables with medium and/or long-term renal function. Among other findings, we confirm that organs from CD have a greater CD68+ macrophage infiltration and we describe that the expression of several proinflammatory and and profibrotic molecules is significantly increased in CD even before grafting. We also observed an increased gene expression of proteins related to graft leukocyte infiltration, mainly macrophages, such as MCP-1 or ICAM-1, as well as of inflammatory mediators such as TNFα or IL1β. We also observed an increased gene expression of macrophage membrane cell receptors related to their inflammatory (M1) or anti-inflammatory (M2) phenotype. Finally, we described a significant increase of IF precursors and mediators in CD. It is noteworthy that multiple parameters (both inflammatory and profibrotic) were associated with the estimated glomerular filtration rate (MDRD) at different times. Multiple regression analysis revealed that delayed renal function as well as graft TGF-β1 gene expression four months after RT were independent predictors of the last renal function control during follow-up (5.8 1.0 years). In conclusion, we confirm the existence of an especially close interconnection between inflammation and fibrosis, especially in the CD RT setting, starting before engraftment and progressing after RT, and that these very early (potentially treatable) factors may already devise its long-term graft prognosis.

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Bigé, Naïke. « Rôle de la Thrombospondine-1 et du récepteur CD47 dans le développement de la fibrose rénale ». Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066705/document.

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La Thrombospondine-1 (TSP-1) représente l'un des principaux activateurs endogènes du TGF-?1 et possède des propriétés anti-angiogéniques et immunomodulatrices. L'un de ses récepteurs, le CD47, joue un rôle critique dans son effet anti-angiogénique et module l'inflammation. Après obstruction urétérale unilatérale (UUO), l'expression de la TSP-1 augmente, est corrélée à celle du TGF-?1 et du collagène III et décroît avec la réparation tissulaire qui accompagne la désobstruction urétérale. L'utilisation de souris knock-out pour la TSP-1 a permis de montrer qu'elle participe au développement des lésions tubulaires rénales en favorisant les altérations vasculaires et le recrutement des cellules inflammatoires. Cet effet pro-inflammatoire dépend, au moins en partie, du facteur chimiotactique MCP-1, de l'augmentation du rolling leucocytaire et de l'activation de la voie Th17. Les souris knock-out pour CD47 bénéficient également d'une protection tubulaire et vasculaire. Cependant, elles présentent une fibrose interstitielle accrue associée à une augmentation de l'expression de la TSP-1 et du TGF-?1 qui pourrait compromettre une éventuelle récupération rénale. L'étude préliminaire de modèles de néphroangiosclérose chez le rat et la souris révèle que la TSP-1 est surexprimée dans le parenchyme rénal au cours de l'hypertension artérielle. L'intensité de son expression est corrélée à la sévérité des lésions histologiques, suggérant son rôle physiopathologique. Ces résultats montrent que la TSP-1 et le récepteur CD47 participent au développement de la fibrose rénale et représentent donc des cibles thérapeutiques potentielles au cours des maladies rénales chroniques
Thrombospondin-1 (TSP-1) is a major endogenous activator of TGF-β1 and has anti-angiogenic and immunomodulatory properties. One of its partners, receptor CD47, plays a critical role in its anti-angiogenic activity and also regulates inflammation. After unilateral ureteral obstruction (UUO), TSP-1 expression increases, correlates to TGF-β1 and collagen III expression and decreases with renal repair after desobstruction. Use of TSP-1 knock-out mice allowed us to demonstrate that TSP-1 favours renal injury by increasing vascular lesions and inflammatory cells recruitment. This pro-inflammatory effect depends, at least in part, on chemotactic factor MCP-1, increasing in leukocyte rolling and engagement of T cells in Th17 pathway. CD47 knock-out mice also benefit from tubular and vascular protection after UUO. However, they exhibit increased interstitial fibrosis associated with higher expression of TSP-1 and TGF-β1, which could compromise renal repair. Preliminary study of nephroangiosclerosis models in rats and mice revealed that TSP-1 expression is induced in renal tissue by arterial hypertension and is correlated to the severity of histological lesions, suggesting its physiopathological role. These results show that TSP-1 and CD47 are involved in renal fibrosis and that they represent potential therapeutic target in the management of chronic kidney disease

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Pat, Betty Kila. « Signal transduction pathways in renal fibrosis / ». St. Lucia, Qld, 2003. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe17739.pdf.

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Winbanks, Catherine, et winbanks@unimelb edu au. « Novel Aspects of Renal Tubulointerstitial Fibrosis ». RMIT University. Medical Sciences, 2007. http://adt.lib.rmit.edu.au/adt/public/adt-VIT20080617.143850.

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Tubulointerstitial fibrosis is the key histological predictor of the progression of declining renal function and the final common pathway of progressive kidney disease, regardless of aetiology. Despite its significance, there are currently no treatments available to abrogate this process and those that suffer with this burden eventually succumb to renal failure. Tubulointerstitial fibrosis is largely mediated by fibroblasts and myofibroblasts present in the interstitium. In response to injury, activated fibroblasts differentiate into myofibroblasts which serves as a histological hallmark of fibrosis. Myofibroblasts are characterised as the key contributors to interstitial volume and their presence ultimately leads to loss of renal function. The pathological entities leading to fibrosis inextricably depend on complex signalling pathways. Whilst many of the well-known growth factors that exert effects on renal fibroblasts (such as FGF, EGF and PDGF) involve the activation of receptor tyrosine kinases, the intracellular signalling events dictating the response of fibroblasts remain undefined. The kinase mTOR, responsible for integrating stress and amino acids and controlling cell growth, is increasingly recognised for its ability to integrate growth factor signals mediated through the upstream serine/threonine kinase PI3K. A number of recent studies have highlighted the role of PI3K and mTOR in the regulation of key events relevant to fibrosis, serving as a basis for Chapter 3: The role of PI3K and mTOR in the regulation of fibroblast proliferation and collagen synthesis, and the first part of Chapter 5: The role of PI3K and mTOR in the regulation of myofibroblast differentiation. These studies have identified a key role for PI3K and mTOR in the regulation of fibroblast proliferation, differentiation and collagen synthesis. The work described within has also attempted to examine the derivation of myofibroblasts via EMT. EMT is a process that is integral to embryogenesis and may act as an important source of myofibroblasts during fibrosis. This process is examined in Chapter 4: Development and validation of an ex vivo model of EMT. This model aims to better represent the in vivo environment and has also been used to identify novel regulators involved in EMT being utilised in the second part of Chapter 5: The role of PI3K and mTOR in EMT. Although cytokines and growth factors are thought to be chiefly responsible for tubulointerstitial fibrosis, we now know that serine proteases of the coagulation cascade may also play roles in renal disease. However, unlike their role in glomerular diseases, the role of coagulation in tubulointerstitial fibrosis is less well-known. The work described in Chapter 6: Constituents of the coagulation cascade are spatially and functionally related to experimental tubulointerstitial fibrosis has examined temporal and spatial in vivo relationships of coagulation factors and markers of fibrosis that aid our understanding of mechanisms of fibrosis. The aim of this thesis was to examine those facets of renal fibroblast function that are most devastating to renal function and culminate in an expansion of the renal interstitium during fibrosis. This work hopes to provide useful information to aid the understanding of the multifaceted mechanisms involved in renal tubulointerstitial fibrosis.

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Krupa, Aleksandra. « Role of microRNAs in renal fibrosis ». Thesis, Cardiff University, 2010. http://orca.cf.ac.uk/54361/.

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This thesis examines the role of microRNAs in renal fibrosis. MicroRNAs constitute a large family of approximately 22-nucleotide-long non-coding RNAs, that in animal cells regulate gene expression posttranscriptionally. At the start of the project, microRNAs were emerging as potentially important factors in various physiological and pathological processes however, there was very little known about their expression and function in the kidney, in particular in tubulointerstitial fibrosis. In this thesis, global microRNA expression has been analysed in vitro in proximal tubular epithelial cells, and in vivo in formalin-fixed, paraffin-embedded kidney biopsy samples from patients with diabetic nephropathy. Among microRNAs altered by profibrotic stimuli, the greatest difference has been found in expression ofmiR-192, which is downregulated in severe diabetic nephropathy. Further examination of miR-192 in kidney biopsy samples has revealed that its expression correlates well with renal function and inversely correlates with fibrosis. A possible function of miR-192 has been then studied in vitro in proximal tubular epithelial cells. It has been found that treatment of the cells with the profibrotic cytokine TGF-β1 downregulates miR-192. Moreover, manipulation of miR-192 expression has shown that miR-192 is involved in E-cadherin regulation. The mechanism of that regulation has been investigated, pointing to two transcriptional repressors of E-cadherin, ZEB1 and ZEB2, as direct targets of miR-192. The presented data suggest that, in the kidney, miR-192 may prevent epithelial-to-mesenchymal transition, known to contribute to renal fibrosis. In parallel, global microRNA downregulation in proximal tubular epithelial cells has been attempted. However, knockdown of Dicer or TRBP, proteins involved in microRNA processing, has not been sufficient to induce changes in microRNA expression. The possible explanations have been discussed. Finally, microRNA role in direct regulation of TGF-β1 synthesis has been investigated. In particular, human microRNAs similar to viral hsv-miR-LAT, reported to directly target TGF-β1 mRNA, have been tested.

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Peters, Harm. « Wirkungen der L-Arginingabe bei immun-vermittelter akuter und chronischer Glomerulofibrose ». Doctoral thesis, [S.l.] : [s.n.], 2000. http://deposit.ddb.de/cgi-bin/dokserv?idn=960841733.

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McSorley, Anita D. « Renal stones in adults with cystic fibrosis ». Thesis, University of Manchester, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.509862.

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Baelde, Jacobus Johannes. « Fibrogenesis in progressive renal disease / ». [S.l. : s.n.], 2005. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=014983980&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.

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Contti, Mariana Moraes. « Transplante renal associado a redução de fibrose miocárdica estudo de ressonância magnética / ». Botucatu, 2018. http://hdl.handle.net/11449/180625.

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Orientador: Luis Gustavo Modelli de Andrade
Resumo: RESUMO: A ressonância magnética cardíaca (RMC), usando o T1 nativo, é considerado método não invasivo para avaliar fibrose miocárdica sem necessidade de usar contraste paramagnético. Até o momento não há dados a respeito do T1 nativo após o transplante renal. O objetivo primário deste estudo foi avaliar mudanças no T1 nativo do miocárdio, seis meses após o transplante renal. Foram analisados prospectivamente, 44 pacientes transplantados renais, os quais foram submetidos a 2 exames de RMC (3T): o 1º nos 10 dias inicias do transplante, e o 2º realizado seis meses após. O tempo do T1 nativo foi medido na região médio- septal e diminuiu significativamente de 1.331 ±52 ms (inicial) para 1.298±42 ms, seis meses após o transplante (p = 0,001). Os pacientes foram divididos em 2 grupos segundo o algoritmo de cluster: no cluster-1 (n=30), a massa do ventrículo esquerdo indexada (MVEi) foi menor, e não foi encontrado nenhum paciente portador de diabetes. No cluster-2 (n=14), a MVEi foi maior, e 100% dos pacientes eram diabéticos. A diminuição do T1 nativo foi significativa apenas nos pacientes do cluster-1 (p = 0,001). Concluindo, o tempo de T1 nativo do miocárdio diminuiu significativamente seis meses após o transplante renal, fato que pode estar associado com regressão da fibrose reativa. O grupo de pacientes que apresentou maior prevalência de diabetes e maior MVEi não alcançou diminuição do T1. ABSTRACT: The measurement of native T1 through cardiac magnetic resonance (CMR) is a noni... (Resumo completo, clicar acesso eletrônico abaixo)
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Nawafa, Lotfia Shames Omar. « The contribution of methyltransferases/demethylases to renal fibrosis ». Thesis, University of Newcastle upon Tyne, 2018. http://hdl.handle.net/10443/4111.

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TGF β-1 signalling regulates many cellular processes, including proliferation, differentiation, apoptosis, immune responses, and fibrogenesis. The essential role of TGF β-1/SMAD signalling in stimulating fibrogenic cells to produce extra cellular matrix proteins and promoting proliferation of myofibroblasts is widely recognised. SMAD3 is known as a mediator in TGF β- 1-induced fibrosis in the kidney. Upon activation of TGF-β receptors, SMAD2 and SMAD3 are phosphorylated and form cytoplasmic heteromeric complexes with SMAD4. These complexes translocate to the nucleus where they regulate expression of TGF β-1 target genes. Tissues undergoing fibrosis exhibit markedly increased expression of a-SMA and interstitial matrix components, such as collagen and fibronectin which are TGF β-1/SMAD3-responsive genes. The mechanism by which SMADs mediate transcriptional regulation of these genes is incompletely understood, however SMAD3-null mice are protected against renal tubulointerstitial fibrosis, glomerular sclerosis, and also fibrosis in other organs. Data from this thesis has demonstrated for the first time that methylation might be important in the regulation of SMAD3 transcriptional activity; indeed the introduction of siRNAs targeting demethylases/methyltransferases led to changes in SMAD3 transcriptional activity. The introduction of siRNAs targeting both methyltransferases and demethylases resulted in changes in α-SMA and fibronectin expression at the protein level. The work in this dissertation again confirms that TGF β-1 signalling is a SMAD3- dependent pathway. SET9 is a methyltransferase enzyme that can methylate non-histone protein substrates including the transcription factors p53, Stat3, Rb, TAF10, E2F1, ERα, NF-κB, and DNMT1. I show that SET9 plays a central role in regulating SMAD3 activity, as shown by SET9 knockdown. I also show that wild type SET9 overexpression results in increased SMAD3 activity, in the presence of TGF β-1. Conversely, expression of a mutant SET9, which lacks methyltransferase activity, 15 failed to increase SMAD3 activity, even in the presence of TGF β-1. Furthermore, SET9 gene silencing with siRNAs significantly attenuated TGF β-1-induced ECM gene expression. These novel effects of SET9 warrant further evaluation of SET9 as a target in the treatment of fibrotic diseases such as CKD. Screening a demethylase siRNA library showed that the putative demethylase HSPBAP-1 is also involved in TGF β/SMAD signalling. Interestingly, I show that HSPBAP-1 interacts with SMAD3, and suppresses the transcriptional activity of SMAD3-driven reporter-genes. This is the first report of such an interaction, and the first data implicating a potential demethylation event in TGF β-1/SMAD3 signalling. Taken together, the work in this study defines novel roles of SET9 and HSPBAP-1 in fibrosis by mediating TGF β-1/SMAD3 signalling. On the basis of my work, future examination of SET9/HSPBAP-1 in whole organism models of renal fibrosis should be considered.

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Vernon, Madeleine Anne. « Myofibroblast loss during renal remodelling ». Thesis, University of Edinburgh, 2013. http://hdl.handle.net/1842/9939.

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Renal fibrosis, the final endpoint of renal disease of any cause, is characterised by myofibroblast deposition of extracellular matrix (ECM) and commonly studied using the unilateral ureteric obstruction (UUO) model. Macrophages are multifunctional cells and involved in renal injury, repair and scarring. Work in other organs has shown that fibrosis is not necessarily irreversible and we established and characterised the murine model of reversible unilateral ureteric obstruction (R-UUO) to investigate the potential reversibility of fibrosis and the underlying mechanism with a particular focus upon the role of macrophages. Reversal of UUO was performed at day 7 and R-UUO kidneys exhibited rapid and profound loss of α-smooth muscle actin (αSMA) positive myofibroblasts over the subsequent 7 days. Loss of αSMA+ myofibroblasts was accompanied by limited and variable degradation of ECM components including collagens I and III. αSMA/TUNEL double staining suggested that some myofibroblasts underwent apoptosis. Infiltrating macrophages were abundant at D7 UUO and persisted at all time points following reversal, however, there was a reduction in the F4/80+ population at D7 Reversal by flow cytometry. Of the F4/80+ population two distinct subpopulations could be identified, F4/80Hi and F4/80Lo cells. The relative contribution of these macrophage populations to the total renal macrophage pool did not alter in obstruction or reversal. The F4/80Hi population was characterised by increased expression of CD11c and decreased expression of CD11b and Ly6C (F4/80HiCD11cHiCD11bLoLy6CLo), whereas the F4/80Lo population was characterised by increased expression of CD11b and Ly6C and decreased expression of CD11c (F4/80LoCD11cLoCD11bHiLy6CHi). CD11b was decreased in both F4/80+ populations during reversal, with altered Ly6C profiles, indicating that the phenotype of the macrophages in each population is different and may change during reversal. Indeed, macrophages isolated by flow cytometry utilising anti-F4/80-APC conjugated antibodies had altered mRNA profiles with D7 reversal associated with decreased mRNA expression of mannose receptor and TGFβ. Previous work in the liver indicates that macrophages may promote or inhibit tissue scarring. In order to ascertain whether macrophages were involved in the loss of αSMA+ myofibroblasts we depleted macrophages after reversal by either administering diphtheria toxin to transgenic CD11b-DTR mice or antagonising colony stimulating factor-1 (CSF-1), a key macrophage mitogen and growth factor, by administering antibodies to the CSF-1 receptor. Both approaches significantly depleted macrophage infiltration but did not retard the loss of αSMA+ myofibroblasts indicating that myofibroblast loss was macrophage independent. Lastly, we investigated the potential role of tissue stiffness in myofibroblast loss following UUO reversal. Primary renal myofibroblasts were cultured from obstructed kidneys, carefully phenotyped and cultured on matrices of differing stiffness. The susceptibility of myofibroblasts to apoptosis increased as the matrix stiffness fell. These data suggest that the altered mechanical microenvironment of the decompressed kidney may be a key stimulus for the macrophage independent loss of myofibroblasts that follows the reversal of UUO.

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Takase, Masayuki. « Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice ». Kyoto University, 2014. http://hdl.handle.net/2433/188704.

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Newbury, Lucy Jade. « Targeting Ras GTPases in murine models of renal fibrosis ». Thesis, King's College London (University of London), 2015. http://kclpure.kcl.ac.uk/portal/en/theses/targeting-ras-gtpases-in-murine-models-of-renal-fibrosis(01debcfb-6d17-4452-b142-e686eb9d059e).html.

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End stage kidney disease (ESKD) affects over 5300 people. The progression of chronic kidney disease (CKD) to ESKD is characterised by cytokine stimulation, leading to the activation of myofibroblasts, resulting in fibrosis. Kirsten rat sarcoma (KNRas) has a key role in the proliferation of renal fibroblasts in vitro and has been highlighted as a possible target for fibrosis. Previous research in our laboratory showed that inhibiting KNRas in the UUO model inhibited renal fibrosis. The aim of this thesis was to investigate the outcome of inhibiting KNRas using Antisense Oligonucleotide (ASO) in the novel Chronic Folic Acid Nephropathy (CFAN) model to study the effect on both fibrosis and renal function. The effect of inhibiting KNRas was also investigated in vitro, to try and elucidate the mechanism by which KNRas controls the progression of fibrosis. KNRas knockdown with ASO143 resulted in 50% reduction in KNRas mRNA which was associated with: 37%-50% reduction in total collagen and protection of renal function (BUN) in the 12 week CFAN model. TGFβ1 treated cells showed an upN regulation i KNRas, Jag1 and Collagen 1a mRNA. Treatment with KNRas ASO was associated with a 3.5 fold reduction in Jag 1 and a 55% reduction in collagen 1a. Jag 1 has been linked to the progression of renal fibrosis via biNdirectional signalling with Notch 1. In conclusion, ASO knockdown of KNRas inhibits fibrosis in vitro and in vivo, and in some instances protects renal function. These results support the hypothesis that KNRas targeting may be beneficial in the treatment of renal fibrosis. Further work is required to further understand the relationship between Jag 1,Notch 1 and KNRas, but this data suggests that KNRas affects renal fibrosis in a Jag 1 dependent pathway.

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Sharpe, Claire Catherine. « The role of the Ras monomeric GTPases in renal fibroblast proliferation ». Thesis, King's College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.271197.

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LAVAUD, STEPHANIE. « Mediateurs de la fibrose renale : etude che zle rat zucker et chez l'homme ». Paris 6, 1997. http://www.theses.fr/1997PA066418.

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Le rein subit des alterations morphofonctionnelles, plus ou moins importantes, au cours du vieillissement, caracterisees principalement par une glomerulosclerose diffuse, des lesions de hyalinose segmentaire et focale des glomerules, des lesions tubulaires et une fibrose interstitielle. Dans un premier temps, par des techniques d'histologie, de biologie moleculaire et de morphometrie, nous avons montre que, chez le rat zucker obese, les lesions de glomerulosclerose apparaissent entre 6 et 9 mois et qu'elles s'accompagnent d'une augmentation de taille des glomerules due a une forte expansion du domaine mesangial. Cette expansion resulte d'une augmentation de la synthese des arn messagers du collagene iv et de la fibronectine et a une diminution du catabolisme de ces proteines matricielles. Une petite augmentation du nombre de macrophages glomerulaires est observee a 1 mois chez les rats obeses mais sans qu'une sur-expression des arnm de facteurs chimiotactiques et de molecules d'adhesion susceptibles de recruter les cellules inflammatoires ne soit notee a cette periode. L'hyperlipidemie, tres accentuee chez les rats obeses des 1 mois, pourrait jouer un role important dans le declenchement des lesions. Dans un deuxieme temps, nous avons etudie les phenomenes de sclerose interstitielle, d'inflammation et les facteurs impliques dans la fibrose. Nous avons quantifie l'expansion des collagenes interstitiels et montre que de grands amas de collagene i s'accumulent avec l'age chez les rats obeses entre 6 et 9 mois, ce phenomene s'accompagne d'un processus inflammatoire important. La sur-expression d'arnm pour la fibronectine, le collagene de type iii, le tgf-1 et l'osteopontine apparait des 3 mois et precede l'afflux de macrophages, la proteinurie, l'alteration tubulaire et la fibrose. Ces deux etudes montrent que des phenomenes precoces interviennent dans l'induction des lesions de fibrose chez le rat zucker mais que le processus inflammatoire n'a pas de role-cle precurseur dans ces deux types de lesions. Enfin, nous avons essaye d'aborder le vieillissement renal humain sur la base de pieces de nephrectomies obtenues sur des patients ages de 37 a 85 ans. Les resultats indiquent que les modifications morphologiques et fonctionnelles observees lors du vieillissement chez l'homme sont pas tres marquees.

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Block, Daniel Bueno 1982. « Fumo em ratas grávidas : envolvimento do fator induzível por hipóxia (HIF-1alpha), do fator de crescimento do endotélio vascular (VEGF) e da eritropoietina (EPO) sobre a ontogênese renal e a função renal da prole de ratos machos ». [s.n.], 2013. http://repositorio.unicamp.br/jspui/handle/REPOSIP/309930.

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Orientadores: José Antonio Rocha Gontijo, Flávia Fernandes Mesquita Vieira
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
Made available in DSpace on 2018-08-24T00:59:05Z (GMT). No. of bitstreams: 1 Block_DanielBueno_M.pdf: 3824410 bytes, checksum: 3f680ece69f85c5b515f67c4ee1f67b4 (MD5) Previous issue date: 2013
Resumo: O ambiente em que vivemos tem grande influência no desenvolvimento e na vida adulta do feto, sendo que a alimentação ou o tabagismo vêem como hábitos e estilo de vida que estão diretamente relacionados a modificações na organogênese fetal. O tabagismo é um dos fatores de maior preocupação das autoridades em saúde pública, devido aos graves problemas à saúde causados pelo cigarro, os custos sociais e econômicos decorrentes destas afecções e, atualmente às possíveis implicações epigenéticas dada incidência do tabagismo em gestantes que pode repercutir sobre gerações futuras. Vários estudos tratam dos efeitos danosos e das repercussões do cigarro no organismo de gestantes e no desenvolvimento do feto, tais como hipertensão arterial, doenças cardiovasculares, maior prevalência de aborto espontâneo, morbidade intrauterina , retarde no crescimento fetal, entre outros. A inalação de monóxido de carbono (CO) pelas gestantes, através do cigarro, causa no feto um estado de hipóxia que pode ser, muitas vezes, fatal. Em resposta a este déficit de oxigênio alguns mecanismos fisiológicos podem ser observados, como: o aumento da expressão do hormônio endógeno eritropoietina (EPO) que regula a eritropoiese e consequentemente, os níveis de hemoglobina e a hematose dos tecidos. O fator induzível por hipóxia (HIF-1) atua na regulação da expressão EPO, sobre a angiogênese, e na viabilidade e proliferação celular vascular entre outras funções. Nesta emaranhada rede de estímulos, está intimamente envolvido o fator de crescimento do endotélio vascular (VEGF) que tem na hipóxia um dos principais estímulos a sua expressão. Este fator é o mais importante mediador do desenvolvimento vascular renal, principalmente do processo de diferenciação do corpúsculo glomerular. Observamos que a inalação de tabaco não modificou significativamente a evolução da massa corporal das mães durante a prenhes (figura 6). No entanto, a prole de animais submetidos ao fumo apresentou uma expressiva redução da massa corporal ao nascer - Ct 7,2± 0,05DPM g vs. Fm 6,3± 0,24DPM g (figura 7), e da nona e décima semana de vida - Ct 322± 20,5DPM g vs. Fm 286± 32,3DPM g e Ct 329± 20,4DPM g vs. Fm 294± 32,6DPM g, respectivamente (figura 8). Os resultados referente à função renal na prole Ct e Fm na 5ª semana de vida não mostraram diferenças significativas na filtração glomerular (CCr) tão pouco na reabsorção proximal de sódio. Contudo, a prole Fm apresentou um aumento significativo na excreção de sódio (FENa+ 24,5%, FEK 13,8%, FEPPNa+ 25,3% e CENa+ 20%) quando comparado ao Ct (figura 13). Por outro lado, na 10ª semana de vida, observamos um aumento significativo (p=0,01) no CCr - 13,9% e na CENa+ - 17,7%, na prole Fm vs. Ct. Nestes animais não houve diferença na reabsorção de Na+ no túbulo proximal e pós-proximal, consequentemente não observamos diferenças significativas na FENa+ e FEK (figura 14). Nos animais Fm de 13 semanas de vida nenhum dos parâmetros das provas funcionais renais se alteraram (figura 15). Contudo, estritamente nesta idade podemos observar um elevação na pressão arterial (p=0,02) entre os grupos Ct e Fm - 134± 9,79DPM mmHg e 146± 11,07DPM mmHg, respectivamente (figuras 11). Não observamos modificações significativas, através da estereologia renal, no volume renal (Ct 0,12 ±0,01 vs. Fm 0,11 ±0,004), na massa renal (Ct 0,43 ±0,03 vs. Fm 0,37 ±0,01) nos animais com 12 dias de vida. Embora, não estatisticamente significativo, a prole Fm apresentou uma redução de 10% no volume glomerular (Ct 16420 ±2411 vs. Fm 15860 ±1078) e 8,2% menos glomérulos (Ct 10450 ±2030 vs. Fm 8628 ±900) quando comparados ao Ct (figuras 16 a 19). Os resultados quantitativos das proteínas envolvidas na angiogênese e eritropoiese - VEGF e EPO, dados pelo ensaio de western blotting, não apresentaram diferenças significativas entre os grupos (figuras 20 a 22). Contudo, os resultados semi-quantitativos por imunolocalização mostrou uma elevada intensidade fluorocrômica do VEGF nos animais Fm e de HIF1? nos animais Ct no período embrionário - E17 (figuras 23 a 27). Observamos, também, uma expressiva modificação na estrutura da matriz extracelular por deposição de proteínas no sitio intersticial e perivascular renal nos animais Fm de 16 semanas vida comparadas ao Ct dadas pela histoquímica de picrossíruis e imunofluorêscencia de fibronectina (figura 29 a 32). Assim, podemos concluir que, a exposição intrauterina ao fumo e seus componentes, podem levar a uma modificação morfofuncional renal na vida adulta que reflete diretamente na manutenção da pressão arterial
Abstract: Prior study about developmental plasticity hypothesis suggests that various adverse intra-uterine exposures lead to persistent fetal developmental adaptations. Maternal smoking is a very important modifiable adverse fetal exposure in western countries and leads to a decrease in the offspring's birth weight. Thus far, the specific adverse fetal smoking exposures and mechanisms underlying these associations on renal development and functional disorder are unclear. The present study investigates, in adult male rats, the effect of smoking exposure (Sk) in utero on blood pressure (BP), and its association with nephron structure and function changes. In the current study, showed in 13-week old Sk offspring enhanced arterial blood pressure, reduced nephron number are associated with higher TGF-?1 glomerular expression. Sk glomeruli also presented an upregulated collagen and fibronectin deposition intrinsically related to fibrotic process as compared to age-matched control group. From our present knowledge, these are the first data showing renal morphological and functional modifications in the gestational smoking model of fetal programming. The fetal-programmed adult rats showed structural kidney disorders associated with a striking stage of fibrosis, which led us to state that the glomerular overflow and subsequently TGF-?1 activity inducing fibrotic protein expression that may cause glomerular EMT
Mestrado
Fisiopatologia Médica
Mestre em Ciências

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Glanville, Michael. « The molecular basis of renal tubular anion secretion ». Thesis, University of Newcastle Upon Tyne, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.273477.

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Lecru, Lola. « Les récepteurs cannabinoïdes : une nouvelle cible thérapeutique de la fibrogenèse rénale ». Thesis, Paris 11, 2014. http://www.theses.fr/2014PA11T088.

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L’insuffisance rénale chronique et la dysfonction chronique de l’allogreffe (DCA) sont associées à la fibrogenèse rénale, qui représente un enjeu majeur en santé publique et nécessite l’exploration de nouvelles cibles thérapeutiques. Dans ce contexte, nous avons étudié l’expression des gènes modulés au cours d’un modèle reconnu de fibrogenèse chez la souris (le modèle d’obstruction urétérale unilatéral, ou OUU). L'expression du gène codant pour le récepteur cannabinoïde apparait sept fois augmentée dans les reins pathologiques comparée à leurs contrôles internes. L’expression du récepteur est également significativement augmentée dans plusieurs types de néphropathies et au cours de la DCA chez l’homme. Le système cannabinoïde se compose de deux types de récepteurs, le type 1 (CB1) et le type 2 (CB2). Ceux-ci jouent des rôles opposés au cours de la fibrose hépatique, suggérant que l’inactivation de CB1 et l’activation de CB2 pourraient constituer une thérapeutique anti-fibrosante d’intérêt, indépendamment de leur implication dans le syndrome métabolique. Ainsi, nous avons montré pour la première fois que le blocage de CB1 par invalidation génétique ou par inhibition pharmacologique permet une réduction significative de la fibrose rénale induite par OUU. La potentialisation de cet effet par l’administration d’un agoniste sélectif de CB2 ne semble en revanche pas relevante, illustrant le rôle prédominant de CB1 dans ce modèle. L’étude du mécanisme réalisée in vitro sur des myofibroblastes primaires activés au TGF-β1 révèle une expression de CB1 augmentée, associée à une synthèse de collagènes significativement bloquée après un traitement par un antagoniste sélectif de CB1. Ceci suggère que l’effet anti-fibrosant dépendant de CB1 agit directement sur le myofibroblaste. Ainsi, nos travaux montrent pour la première fois l’effet anti-fibrosant de l’inactivation de CB1, avec une action directe sur la cellule effectrice de la fibrose, suggérant que CB1 représente une nouvelle cible thérapeutique et un médiateur majeur de la fibrose rénale. Son expression dans les néphropathies humaines des reins natifs présente une forte corrélation avec le taux de créatinine et pourrait constituer un nouveau biomarqueur d’atteinte rénale
Chronic kidney disease, secondary to renal fibrogenesis, is a burden on public health. In the present study, we show that the cannabinoid 1 receptor (CB1) may be a new pathway in renal fibrogenesis, independently of its involvement in metabolic disease. We found that CB1 expression was highly expressed in kidney biopsies of patients suffering from IgA nephropathy, diabetes, and acute interstitial nephritis. We also used an experimental model of renal fibrosis, the unilateral ureteral-obstruction model, in mice. Both genetic and pharmacological invalidation of CB1 induced a profound reduction in renal fibrosis, showing its prominent role in renal fibrosis. Cannabinoid receptor 2 is also involved in renal fibrogenesis but does not potentialize the role of CB1. CB1 expression is drastically increased in myofibroblasts upon TGFß-1 stimulation. The decrease in renal fibrosis during CB1 invalidation is explained by a direct action on myofibroblasts: CB1 blockade reduced collagen expression in vitro. In addition, CB1 also modulates the macrophage infiltrate responsible for renal fibrosis in unilateral ureteral obstruction through a decrease in MCP1 synthesis, a major chemoattractant cytokine. Our study strongly suggests a major role for CB1 in the activation of myofibroblasts, which are the main effector cells in renal fibrogenesis, and suggests that CB1 may represent a major new target for treating chronic kidney disease

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Yokoi, Hideki. « Role of connective tissue growth factor in renal tubulointerstitial fibrosis ». Kyoto University, 2005. http://hdl.handle.net/2433/144757.

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Braga, Tárcio Teodoro. « Participação de diferentes subtipos de macrófagos e a contribuição do ácido úrico solúvel, dos receptores TLR2 e TLR4 e das moléculas MyD88 e NLRP3 para o desenvolvimento da fibrose renal ». Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/42/42133/tde-24092014-184133/.

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A doença renal crônica é uma doença mediada pelo sistema imune e caracterizada por fibrose. Camundongos deficientes em TLR2, TLR4, MyD88 e NLRP3 se mostraram protegidos frente ao dano renal e à deposição de colágeno após serem submetidos à obstrução unilateral do ureter (UUO). Além disso, os camundongos protegidos exibiram menor produção de citocinas relacionadas com um perfil imune Th2 e apresentaram menor acúmulo de macrófagos do subtipo M2. Inicialmente, creditamos aos macrófagos M2 o papel de macrófagos formadores de fibrose uma vez que tal subpopulação é encontrada em maior número aos sete dias após a UUO em animais WT, porém, vimos que os personagens centrais no desenvolvimento da fibrose são macrófagos M1, encontrados no início da lesão renal. Também vimos que o ácido úrico é a molécula capaz de induzir a troca de fenótipo de M1 para M2 ao longo da UUO, além de ser capaz de ativar a via do inflamassoma. O ácido úrico solúvel é liberado em um contexto de hipóxia e ativa o complexo do inflamassoma NLRP3 por mecanismos diferentes, mas complementares.
Chronic kidney disease is an immune mediated disease characterized by fibrosis development. The damaged tissue releases molecules such as soluble uric acid resulting from the degradation of extracellular matrix or dead cells, which activate TLR and NLR, leading to the translocation of MyD88 in many cell types. This modulation of the immune system interferes with the activation of different subtypes of macrophages and activity of CD4+ T cells, with the Th1/Th2 paradigm as a possible effector mechanism of fibrosis. TLR2, TLR4, MyD88, and NLRP3 deficient mice are protected against renal damage and collagen deposition after being submitted to unilateral ureteral obstruction (UUO), when compared to wild type animals. Moreover, protected mice exhibited less production of Th2 related cytokines and reduced accumulation of M2 macrophages. Initially, we hypothesized M2 macrophages are responsible for fibrosis formation since this subset is found in greater numbers seven days after UUO in WT mice, however, we observed the central characters on the development of fibrosis are M1 macrophages found in the onset of renal injury. These data were confirmed by the injection of Stat6 KO M1 macrophages into Rag deficient mice previously depleted of macrophages and subjected to UUO, in which we observed higher proteinuria and increased collagen deposition. We also observed that uric acid is able to induce the exchange of phenotype from M1 to M2 along the UUO, besides being able to activate the inflammasome pathway. The soluble uric acid is released in the context of hypoxia and activates the NLRP3 inflammasome complex by different, but complementary mechanisms. Therefore, the renal damage releases soluble uric acid, which signals via innate immune receptors, and the damage brings as a consequence the deposition of proteins in the renal interstitium, culminating in fibrosis.

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Klinkhammer, Barbara Mara [Verfasser]. « Zell-basierte Ansätze zur Therapie der renalen Fibrose / Barbara Mara Klinkhammer ». Aachen : Hochschulbibliothek der Rheinisch-Westfälischen Technischen Hochschule Aachen, 2014. http://d-nb.info/1065847890/34.

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Shi, Ying. « Targeting receptor-interacting serine/threonine-protein kinase (RIPK)3 in renal tubulointerstitial fibrosis ». Thesis, The University of Sydney, 2018. http://hdl.handle.net/2123/20195.

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Chronic kidney disease (CKD) affects almost 10% of the adult population worldwide. Regardless of the initial cause of renal injury, renal fibrosis is the final common pathway of all forms of CKD, including diabetic kidney disease (DKD). However, current therapies to attenuate the development of progressive renal fibrosis are limited to blockade of the renin-angiotensin-aldosterone system (RAAS), achievement of blood pressure targets and in the case of DKD, blood glucose control. More recently inhibition of sodium-glucose linked transporter-2 has shown impressive renoprotective benefits in secondary analyses of major cardiovascular end-point trials. However, studies, where renal disease is a primary endpoint, are awaited. Given the personal and societal impacts of the increasing burden of CKD, it is of utmost importance to identify novel interventions for preventing the progressive renal fibrosis and thus progressive CKD. Receptor-interacting serine/threonine-protein kinase (RIPK) 3, known as a necroptotic kinase, is recognised to be involved in various innate immune responses, including necroptosis and activation of the toll-like receptor (TLR) 2 and 4 pathways and the pyrin domain-containing protein (NLRP) 3 inflammasome. However, the role of RIPK3 in the development of renal cortical fibrosis, and in particular in the pathology observed in the renal tubule under conditions that stimulate a fibrotic response has not been elucidated. In this thesis, mouse models of folic acid (FA)-induced nephropathy (studied at 28 days) and streptozotocin (STZ)-induced diabetic nephropathy (studied at 24 weeks) were developed. RIPK3 knock out (KO) mice were used to determine the therapeutic effect of RIPK3 in renal fibrosis, and the RIPK3 inhibitor dabrafenib was utilized as a pharmacological inhibitor of RIPK3. Human proximal tubular cells exposed to transforming growth factor beta-β1 (TGF-β1) were used as in vitro model to determine the role of necroptosis in the development of tubular pathology under pro-fibrotic influences. Inflammatory and fibrotic markers, as well as the relevant signalling pathways, were examined. Our results show that blockade of RIPK3 genetically or pharmacologically suppressed FA-induced activation of the TLR2 and 4 pathways, the NLRP3 inflammasome and TGF-β1 expression, associated with a reduced myofibroblast activation and interstitial extracellular matrix (ECM) deposition. RIPK3 inhibition also confers renoprotection in the STZ-induced diabetic nephropathy model. A reduction of TGF-β1, NLRP3 activation and TLR4 but not TLR2 was observed in RIPK3 KO mice. Inhibition of necroptosis also reduced TGF-β1 and ECM secretion in tubular cells exposed to TGF-β1. Collectively, the data shown in the thesis uniquely demonstrate that RIPK3 is involved in the development of renal fibrosis via multiple pathways, including necroptosis, TLR2 and 4 signalling and activation of the NLRP3 inflammasome. Given the two strategies to inhibit RIPK3 converge on inhibition of the TLR4 pathway and the NLRP3 inflammasome activation, we consider these are key pathways to inhibit to confer renoprotection. Dabrafenib, the RIPK3 inhibitor, deserves further exploration for repurposing as a targeted renal therapy.

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Jan, Budour H. 1984. « The Role of Kindlin-2 in the progression of renal fibrosis ». Doctoral thesis, Universitat Pompeu Fabra, 2017. http://hdl.handle.net/10803/543848.

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Chronic kidney disease (CKD) is usually characterized by histological lesions of glomerulosclerosis and tubulointerstitial fibrosis (TIF). The progressive TIF is mediated by multiple mediators such as growth factors, metabolic toxins and stress molecules. One of the key mediators of this process is TGF-1 that induces cellular responses in a wide variety of cell types. In renal tubular cells TGF-1 activation requires the binding of Kindlin-2 to the TGF-1 receptor. The expression of Kindlin-2 was assessed in three different situations and correlated with the progression of the renal fibrotic process. After 48 hours, 7 days and 45 days of ischemic lesion, mouse cortical tissue expressed Kindlin-2 in similar level through the progression of the fibrotic process. In human biopsies presenting histological characteristic of acute tubular necrosis (ATN), Kindlin-2 was also increased and showed high expression in tubules. Smooth muscle cells from arteries showed decreased expression as compared to the biopsies without ATN characteristics. Kindlin-2 is demonstrated to be activated in a very early time after injury and will likely to keep the progression of the fibrotic lesion of the kidney
La enfermedad renal crónica (ERC) se caracteriza habitualmente por lesiones histológicas relacionadas con la glomeruloesclerosis y la fibrosis tubulointersticial (FTI). La progresión de la FTI se induce por múltiples mecanismos moleculares como factores de transcripción, toxinas metabólicas y moléculas de estrés. Uno de los mediadores clave en esta progresión es TGF-1 que induce respuestas en gran variedad de tipos celulares. En las células tubulares renales, la activación del TGF-1 requiere la unión de Kindlin-2 al receptor de TGF-1. La expresión de Kindlin-2 se testó en tres condiciones de lesión distintas y se encontró su correlación con la progresión del proceso fibrótico renal. Después de 48 horas, 7 días y 45 días tras una lesión isquémica, el tejido renal de ratón expresó Kindlin-2 de una forma similar durante la evolución del proceso fibrótico. En las biopsias humanas con características compatibles con la necrosis tubular aguda (NTA), Kindlin-2 se detectó en varias zonas del tejido renal. Se describió una alta expresión en túbulos y en células de músculo liso de las arterias se encontró disminuido. Este perfil fue opuesto en las biopsias sin características histológicas de NTA. Kindlin-2 está activado en los procesos más inmediatos en la lesión y se mantiene a lo largo de la progresión, asumiendo un papel necesario en este proceso.

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Kapoor, Rishab. « Investigating the mechanisms of renal fibrosis following ischaemia and reperfusion injury ». Thesis, University of Newcastle upon Tyne, 2018. http://hdl.handle.net/10443/4117.

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Ischaemia-reperfusion injury (IRI) is the major cause of acute kidney injury (AKI) and predisposes to the development of chronic kidney disease (CKD). The role of TGF-β in extracellular matrix deposition and renal fibrosis has been well established. This study was designed to establish an in vitro model of renal tubular IRI, evaluate the role of TGF-β in IRI in human proximal tubular epithelial cells (HKC8 and HK2 cells) and further determine the role of αvβ6 integrin in IRI. Initially an in vitro model of hypoxia and free radical stress by treating HKC8, HK2 and fibroblasts (MRC-5 cells) with CoCl2 and H2O2 respectively was established. These treatments led to pro-fibrotic changes characterised by increased expression of fibrotic marker α-SMA and reduced expression of epithelial cell marker E-Cadherin at mRNA and protein level. Binding of TGF-β to its receptor leads to activation of the kinase ALK5. ALK5 inhibition prevented the changes induced by H2O2 or CoCl2 suggesting the involvement of TGF-β to the cellular response to IRI. To confirm that TGF-β is released after treatment of cells to mimic IRI, media transfer and co-culture studies were performed. These experiments confirmed that bioactive TGF-β was being released. Lastly, the role of αvβ6 integrin was studied post H2O2 or CoCl2 treatment. Expression of αvβ6 integrin was elevated in conditions mimicking IRI in vitro and in biopsy samples acquired from patients with acute tubular necrosis and in mouse kidney following IRI. Knockdown of αvβ6 integrin in HKC8 cells decreased the bioavailability of active TGF-β following CoCl2 or H2O2 treatment and therefore the pro-fibrotic changes that were seen. This study confirms that bioactive TGF-β is produced following IRI and αvβ6 plays an important role in its release.

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Oguntona, Taiwo Shola. « The potential role of a carboxypeptidase B2 inhibitor in renal fibrosis ». Thesis, University of Sheffield, 2018. http://etheses.whiterose.ac.uk/19949/.

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Diabetic nephropathy (DN) is a fibrotic disease from renal injury which is characterized by extracellular matrix (ECM) build-up. Thus, DN leads to disruption of renal architecture and loss of renal function. We hypothesized that renal fibrosis can be improved by increasing plasmin activity through inhibition of carboxypeptidase B2 (CPB2) activity using UK-396082- a selective CPB2 inhibitor. An in vivo rat model of DN was used. Unilateral nephrectomy and induction of type 1 diabetes with 80mg/kg streptozotocin injection. Blood glucose was maintained between 20-25 mM for 8 months with linplants. The rats were divided into 3 groups. Group 1 (diseased) fed on normal chow. Group 3 (treatment) fed on normal chow for four months after which it was changed to chow mixed with 0.3g/kg of UK-396082 for the final four months. Group 2 (prophylaxis) fed on chow mixed with a 0.3g/kg of UK-396082 for 8 month. In an in vitro study CPB2, plasmin, tissue–type (tPA) and urokinase-type (uPA) plasminogen activators were assayed in the presence and absence of UK-396082 in rat kidney epithelial-like, fibroblast-like and mesangial cells cultured on plastic and fibrin gel. Our results confirmed DN in this rat model. Prophylactic administration of UK-396082 gave protection against development of kidney fibrosis and impaired kidney function. However, with advanced DN, UK-396082 appeared to have little protective effect. The In vitro results demonstrated that CPB2, tPA, uPA and plasmin activities were present in rat kidney epithelial-like, fibroblast-like and mesangial cell culture. CPB2, tPA, and plasmin activities were increased when epithelial and mesangial rat kidney cells were cultured on fibrin as opposed to plastic. Both epithelial-like and mesangial cells in the presence of fibrin led to more plasmin generation in the presence of UK-396082.

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Oliveira, Fabiana Aparecida Mayrink de. « O efeito do laser de baixa intensidade na fibrose intersticial renal ». Universidade Federal de Juiz de Fora, 2011. https://repositorio.ufjf.br/jspui/handle/ufjf/2129.

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Justificativa e Objetivo: Independente da etiologia, a doença renal crônica (DRC) envolve fibrose generalizada e progressiva do tecido, atrofia tubular e a perda da função renal. Atualmente, as terapias eficazes para esta condição são escassas. Neste estudo, foram investigados os efeitos da terapia laser de baixa intensidade (LLLT) sobre a fibrose intersticial, que ocorre após obstrução ureteral unilateral (OUU) em ratos, um modelo experimental de doença renal crônica. Materiais e Métodos: Foram utilizados 32 ratos Wistar, 8 em cada grupo, machos, com 250 a 300g de peso aproximadamente e 8 semanas de idade. O rim obstruído de metade dos ratos, submetidos à OUU receberam dose única intra-operatória do LLLT (AlGaAs laser, 780 nm, 22,5 J / cm ², 30 mW, 30 segundos em cada um dos nove pontos). Após 14 dias, a fibrose renal foi avaliada pela coloração por picrosírius e medição da área transversal sob luz polarizada. Análise imunohistoquímica quantificou células do tecido renal que expressam marcadores de fibroblastos (FSP-1) e miofibroblastos (α-SMA). RT-PCR foi realizado para determinar a expressão de mRNA de genes chaves relacionados com a fibrose: TGF-β1, Smad3 e colágeno I (Col I). Resultados: No grupo OUU e tratado pelo LLLT os animais apresentaram menos fibrose renal do que os animais obstruídos (OUU). α-SMA, TGF-β1 e Smad3 foram aumentados no interstício renal de ratos OUU. LLLT reduziu a expressão de todas essas moléculas. LLLT não parece ter um efeito significativo no Col I ou FSP-1, que também foram induzidos por OUU. Conclusão: Pela primeira vez, nós mostramos que LLLT tem um efeito protetor em relação à fibrose intersticial renal. Entende-se que, atenuando a inflamação, a laserterapia pode impedir a ativação tubular e transdiferenciação, que são os dois processos principais que formam a fibrose renal no modelo OUU.
Background and Objective: Regardless of the etiology, chronic kidney disease (CKD) involves progressive widespread tissue fibrosis, tubular atrophy and loss of kidney function. At present, effective therapies to this condition are lacking. We investigated the effects of low level laser therapy (LLLT) on the interstitial fibrosis that occurs after unilateral ureteral obstruction (UUO) in rats, an experimental model of CKD. Study Design/Materials and Methods: We used 32 Wistar rats, 8 in each group, males, 250 to 300g weight and 8 weeks old. The occluded kidney of half of the Wistar rats that underwent UUO received a single intraoperative dose of LLLT (AlGaAs laser, 780 nm, 22.5 J/cm², 30 mW, 30 seconds on each of nine points). After 14 days, renal fibrosis was assessed by Sirius red staining and measurement of the cross-sectional area under polarized light. Immunohistochemical analyses quantitated the renal tissue cells that expressed fibroblast (FSP-1) and myofibroblast (α-SMA) markers. RT-PCR was performed to determine the mRNA expression of key fibrosis-related genes, namely TGF-β1, Smad3 and collagen I (Col I). Results: The UUO-LLLT animals had less severe renal fibrosis than OUU animals. α- SMA, TGF-β1 and Smad3 were increased in the renal interstitium of UUO rats. LLLT reduced the expression of all of these molecules. LLLT did not appear to have a significant effect on Col I or FSP-1, which were also induced by UUO. Conclusion: For the first time, we showed LLLT had a protective effect regarding renal interstitial fibrosis. It is conceivable that by attenuating inflammation, LLLT can prevent tubular activation and transdifferentiation, which are the two processes that mainly drive the renal fibrosis of the UUO model.

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Zimmerman, Danielle. « The Role of Angiotensin-(1-7) in a Mouse Model of Renal Fibrosis ». Thèse, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/23692.

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Angiotensin-(1-7) [Ang-(1-7)] is a heptapeptide component of the renin angiotensin system and the endogenous ligand for the Mas receptor. Ang-(1-7) is generated mainly via angiotensin converting enzyme 2 (ACE2)-dependent cleavage of Angiotensin (Ang) II. Studies suggest Ang-(1-7) may protect against progression of renal injury in experimental models of chronic kidney disease, although the responses may be dose dependent. The role of Ang-(1-7) in the progression of renal fibrosis in unilateral ureteral obstruction (UUO) remains unclear. We tested the hypothesis that endogenous Ang-(1-7) and low dose exogenous Ang-(1-7) would protect against renal injury in the UUO model, while high dose Ang-(1-7) would exacerbate renal injury. Male C57Bl/6 mice underwent UUO and received vehicle, the Ang-(1-7) antagonist A779, or one of three doses of Ang-(1-7) for 10 days. Treatment with A779 exacerbated renal injury as seen by increased fibronectin, transforming growth factor-β (TGF-β), and α-smooth muscle actin (α-SMA) expression, increased tubulointerstitial fibrosis scores, macrophage infiltration, apoptosis, and NADPH oxidase activity in obstructed kidneys. Paradoxically, delivery of exogenous Ang-(1-7) was associated with increased renal injury regardless of dose. Taken together, these data indicate the Mas receptor may be sensitive to concentrations of Ang-(1-7) within the obstructed kidney and that exogenous Ang-(1-7) stimulates pro-fibrotic and pro-inflammatory signalling through unclear pathways.

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Pereira, Rafael Canavel. « Influência da sobrecarga de sódio em ratos submetidos à isquemia e reperfusão renal : tratamento com N-acetilcisteína ». Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/5/5148/tde-12092018-090042/.

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A injúria renal aguda (IRA) é uma complicação renal que necessita de tratamento com urgência, gerando gastos de bilhões de dólares na saúde pública de diversos países. Dentre os tipos mais comuns de IRA é a IRA isquêmica causada por perfusão abaixo do normal ao tecido renal, gerando maior produção de espécies reativas de oxigênio (ROS), ativação do sistema renina angiotensina aldosterona (SRAA) local, necrose tubular aguda (NTA). O tratamento com o antioxidante N-acetilcisteína (NAC) tem resultados positivos em diversos modelos de lesão renal. Ao reestabelecer a função renal após a IRA, os pacientes devem seguir dietas restritas quanto a quantidade de proteínas e de sal, entretanto, sabe-se que o sal é um dos maiores causadores de doenças renais e é encontrado de forma exacerbada em diversos tipos de alimentos comumente consumidos no dia a dia. OBJETIVOS: Avaliar os efeitos da sobrecarga de sódio sobre a isquemia e reperfusão renal e verificar se o tratamento com NAC é capaz de mitigar os danos causados pela isquemia e reperfusão renal bilateral associada ao alto consumo de sódio. ANIMAIS: Ratos Wistar machos com seis semanas de vida foram divididos em dois tipos de dieta normossódica (NR) com 2,3% de NaCl e hipersódica (HR) com 8% e submetidos ou não (SHAM) à isquemia e reperfusão renal bilateral e tratados ou não com NAC (600 mg/L) VARIÁVEIS: Peso corpóreo, pressão arterial caudal, consumo hídrico e de ração, volume urinário, fração de excreção de sódio e potássio, sódio, potássio, creatinina e uréia sérica, clearance de creatinina, proteinúria e albuminúria, massas cardíaca e renal, diâmetro transverso glomerular e diâmetro transverso do cardiomiócito, fibrose intersticial renal e cardíaca, TAS,TBARS e ácido úrico, expressão gênica de renina, atividade da renina plasmática e renal, taxa de sobrevida. RESULTADOS E DISCUSSÃO: A dieta hipersódica associada à isquemia e reperfusão induziu ao aumento da albuminúria, das massas renal e cardíaca e ao desenvolvimento de fibrose intersticial cardíaca e renal, não houve diferença na atividade da renina plasmática e renal, e também no estado REDOX destes animais. NAC foi capaz de prevenir o desenvolvimento de albuminúria, o aumento das massas renal e cardíaca e formação de fibrose
ABSTRACT: Acute kidney injury (AKI) is a renal complication that requires urgent treatment and the most common types is ischemic AKI caused by below normal perfusion to renal tissue, generating high production of reactive oxygen species (ROS), tissue renin angiotensin aldosterone system (RAAS) activation, and acute tubular necrosis (NTA). The antioxidant N-acetylcysteine (NAC) treatment have shown positive results in several renal injury models. After reestablishment of renal function, patients should be submitted to protein and salt restriction diet. Salt is known to be a major cause of kidney disease. OBJECTIVES: To evaluate the effects of sodium overload on renal ischemia and reperfusion and to verify if NAC treatment was able to mitigate the damage caused by bilateral renal ischemia and reperfusion associated with high sodium consumption in diet. ANIMALS: Six-week-old male Wistar rats were divided in normal sodium (NS - 1.3% NaCl) or high sodium (HS - 8.0% NaCl) diet group. Both diet group were submitted to bilateral renal reperfusion and ischemia or not (SHAM), treated or not with NAC (600mg/L). VARIABLES: Body weight, tail blood pressure, water and feed intake, urinary volume excretion, sodium and potassium excretion, sodium, potassium, serum creatinine and urea, creatinine clearance, proteinuria and albuminuria, cardiac and renal masses, transverse diameter glomerular and transverse diameter of the cardiomyocyte, renal and cardiac interstitial fibrosis, TAS, TBARS and serum uric acid, renin gene expression, plasma and renal renin activity, survival curve. RESULTS AND DISCUSSION: The high sodium diet associated to ischemia and reperfusion induced to albuminuria; increased renal and cardiac mass and to development of cardiac and renal interstitial fibrosis. However, plasma and renal renin activity and REDOX status were not changed. NAC was able to prevent the albuminuria, renal and cardiac hypertrophy, and fibrosis formation

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Chakrabarti, Shubro. « Mechanisms of fibrosis in feline chronic kidney disease ». Thesis, Royal Veterinary College (University of London), 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.572451.

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Al, Hasan Abd Alrasol. « The role of 6-0-sulphated heparan sulphate in chronic renal fibrosis ». Thesis, University of Newcastle Upon Tyne, 2012. http://hdl.handle.net/10443/1725.

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Heparan sulphate (HS) plays crucial roles during the genesis and resolution of inflammation by sequestration, stabilization and presentation of proinflammatory cytokines and growth factors. The interaction between many of these factors and HS is critically dependent on the variable distribution of anionic 6-O-sulphated glucosamine residues within the structure of HS. The pattern of 6-O-sulphation is generated during HS biosynthesis by HS-6-O-sulphotransferases (HS6STs) but can be modified later by cell-surface HS-6-O-endosulphatases (SULFs). This study was designed to examine the potential contribution of these enzyme families to renal fibrosis following chronic inflammation. Initial experiments showed that the fibrogenic cytokine TGF-β induced SULF2 expression by renal tubular epithelial cells. Immortalized renal tubular epithelial cells were transfected to constitutively overexpress either HS6ST1 or SULF2 in order to examine the effect of these enzymes on cytokine function. Cells which overexpressed HS6ST1 showed increased binding of FGF2 compared to mock transfected control cells; this FGF2 binding correlated with increased pERK expression and enhanced cell proliferation. The requirement for HS for these processes was validated by inhibition of FGF2 binding with soluble HS, heparin or heparitinase III, whilst the importance of HS sulphation for increased binding was demonstrated after treatment of the cells with chlorate. Structural analysis of 35S-labelled HS from HS6ST1 overexpressing cells demonstrated an increase in mono-6-O-sulphated disaccharides accompanied by a decrease in 2-O-sulphated iduronic acid. By contrast, SULF2 transfectants showed reduced FGF2 binding, ERK activation and proliferation. Structural analysis of 35S-labelled HS from these cells showed a 50% reduction in 6-O-sulphation with a parallel increase in mono-2-O-sulfated iduronic acid. The significance of the in vitro study for renal fibrosis was then examined using a murine unilateral ureteric obstruction (UUO) model. Immunochemical analysis of UUO kidney sections showed a significant increase in expression of epitopes containing N- and 6-O sulphated HS around the renal tubules. This change was accompanied by a 5-fold increase in expression of the SULF1 gene. In summary, this study suggests that modulation of the expression of sulphate at the 6-O position in HS plays a significant role in the progression of chronic renal fibrosis by alteration of the biological activity of fibrogenic growth factors.

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Menon, Vasudev Ramdas. « Analysis of the role and regulation of disintegrin metalloproteases in renal fibrosis ». Thesis, University of Glasgow, 2012. http://theses.gla.ac.uk/3872/.

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Chronic Kidney Disease (CKD) affects about 10-20% of the adult population of the developed world. The underlying molecular mechanisms contributing to its varied pathophysiology CKD are still unclear. Without early diagnosis and therapeutic intervention, patients with CKD risk progressing to end stage renal failure (ESRF) requiring renal replacement therapy such as dialysis and eventually a renal transplant. Tubulointerstitial fibrosis is the common end point in most progressive renal diseases and has consistently been shown to be the best histological predictor of progression towards end stage renal failure. This 'point of no return' involves atrophy of the tubulointerstitium, leukocyte infiltration, persistent fibroblast proliferation and activation and dysregulation of extracellular matrix (ECM) resulting ultimately in scarring and loss of function. TGFB initiates and is involved in the entire course of fibrosis pathogenesis. Critical mediators of TGFB regulation are the intracellular signal transducers - the Smads which regulate gene transcription, and the recently discovered small neucleotide RNAs - microRNAs (miRs). miRs are a post transcriptional gene regulatory system and demonstrate distinct spatio-temporal expression and their expression is associated with crucial developmental and pathophysiological processes. Disintegrin metalloproteases (ADAMs) are members of the calss of zinc-ion proteases that can regulate key cellular and acellular processes including chemotaxis, adhesion and fusion, and modulate auto and paracrine signalling pathways by regulating ligand/receptor availability. Therefore, ADAMs can potentially regulate both inflammatory and fibrotic changes associated with renal disease. However, evidence towards the role of ADAMs in renal disease remains largely descriptive. While TGFB regulation of MMPs and TIMPs in renal disease has been well studies, the regulation or mechanisms of action of ADAMs in renal disease remains unknown. This thesis aims to demonstrate the involvement of proteolytically active ADAMs in renal fibrosis and provide mechanistic evidence towards transcriptional and post-transcriptional regulation of these ADAMs by canonical TGFB signalling.

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Soofi, Abdulsalam. « Pathways that regulate renal development, fibrosis, and metabolic disease in mouse models ». Thesis, University of Warwick, 2017. http://wrap.warwick.ac.uk/102838/.

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The kidney is an essential organ that maintains homeostasis, maintains water and mineral balance, and removes metabolic waste products from the body. In mammals, the kidney derives from the intermediate mesoderm (IM) and develops through a multistep process where undifferentiated mesenchyme is converted into a highly complex organ. Several transcriptional regulators, including the Pax2 gene, have been identified in the specification and maintenance of this multistep process. The Pax2 gene marks the IM shortly after gastrulation, when the mesoderm becomes compartmentalized into paraxial, intermediate, and lateral plate. Pax2 expression in the IM distinguishes all of the cells fated to become epithelia in the urogenital tract and is necessary to establish and maintain this phenotype. Pax2 null mutants do develop a nephric duct (Brophy et al., 2001; Soofi et al., 2012), but the duct is completely absent in a Pax2/8 double mutant, suggesting that these Pax genes function redundantly in this early IM domain; however, in Pax2 homozygous mutant mice, the metanephric mesenchyme neither responds to inductive signals nor does the mutant mesenchyme aggregate into early renal vesicles resulting in a lack of kidneys, ureters, and genital track. We describe two new alleles of Pax2 created by inserting the Enhanced Green Fluorescent Protein coding region into the 5' untranslated leader sequence. One allele is a hypomorph that generates less protein and exhibits structural defects in kidneys and ureters upon homozygosity. A second allele is a true null that can be used to image Pax2 expressing cells in a mutant background. Organ culture and embryo analyses point to a loss of epithelial cell polarity and increased mobility in cells that have deleted Pax2 function. These experiments provide new insight into the role of Pax2 protein levels in determining correct renal architecture and cell fate. The prevalence of chronic kidney disease (CKD) worldwide is reflected by the increasing number of people with end stage renal disease (ESRD) requiring some form of renal replacement therapy. The overall incidence of ESRD is increasing at an alarming rate and is correlated with the rise of diabetes, obesity, and hypertension. Yet, effective therapies for chronic fibrosis in the kidney and other tissues are still awaited. Among the most extensively studied signaling pathways in renal fibrotic disease are those of the TGFb superfamily (TGFb and BMPs). Given the critical roles for TGFb and BMP proteins in enhancing or suppressing renal interstitial fibrosis, respectively, the results of this thesis will show how the expression of this secreted protein KCP could diminished renal fibrosis in mouse models of chronic and acute kidney disease. In vivo, KCP-KO mice are viable and fertile but are more sensitive to tubular injury and exhibit significant pathology after recovery. Also, deletion of KCP sensitized mice to developing obesity and associated complications such as liver steatosis and glucose intolerance. In contrast, transgenic mice that expressed KCP in the kidney, liver, and brown adipose tissues were resistant to developing high fat diet induced obesity and had significantly reduced white adipose tissue. This data demonstrates that modulation of the TGFβ signaling with secreted inhibitors or enhancers can alter the profile of adipose tissue, which reduces obesity and impaired the progression of metabolic disease. The Metabolic Syndrome is reaching epidemic proportions in the developed world, primarily due to the increased availability of high caloric foods and the decrease in daily physical activity. Energy balance is critical for maintaining normal body weight and homeostasis. When caloric intake chronically exceeds energy expenditure, white adipose tissue stores excess energy in the form of triglycerides, leading to obesity and related complications such as type-2 diabetes, a condition also referred to as metabolic syndrome which is a condition of chronic sub-clinical inflammation. In mice, the TGFβ superfamily has been implicated not only in the development and differentiation of white and brown adipose tissues, but also in the induction of the pro-inflammatory state that accompanies (Tseng et al., 2008). The work outlined in this thesis suggests that altering the TGFβ superfamily signaling pathway by a secreted protein (KCP) can attenuate renal fibrosis and the negative effects of obesity-associated metabolic syndrome. Providing a conceptual basis for the use of small molecule analogues of KCP to attenuate profibrotic pathways that depend on continued TGFβ signaling and/or counteraction by BMPs may potentially provide a novel approach to translating the protective role of specific BMPs (e.g. BMP-7) into clinical benefit.

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Smith, Stuart William. « The role of CD248+ stromal cells in the pathogenesis of renal fibrosis ». Thesis, University of Birmingham, 2012. http://etheses.bham.ac.uk//id/eprint/3337/.

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Chronic kidney disease affects 10-13% of the population. The dominant processes that promote kidney disease, irrespective of the trigger, occur in the stromal compartment where fibrosis is considered the hallmark of progressive renal disease. Recent studies have highlighted the importance of the vasculature and the role of the renal pericyte as a progenitor of activated matrix-depositing stromal myofibroblasts, cells that drive the development of renal fibrosis. CD248 is a 175 KDa type I transmembrane glycoprotein expressed at low levels in non-inflamed kidney by resident renal stromal cells (pericytes and myofibroblasts). In this thesis I demonstrate that CD248 expression is increased in a cohort of patients with progressive renal fibrosis (n=93). Furthermore, increased CD248 expression in the kidney stroma is an independent risk factor for the progression of renal disease. I have then used an established murine model of renal fibrosis (unilateral ureteric obstruction) to characterise the origin, phenotype and function of CD248+ cells in vitro and in vivo. A transgenic mouse, with a targeted disruption to the CD248 gene has been used to assess the causal role that CD248 plays in the pathogenesis of renal fibrosis. Mice deficient in CD248 are protected against myofibroblast accumulation, tissue fibrosis and microvascular rarefaction following renal injury. In vitro data suggests that this phenotype may be due to a defect seen exclusively in stromal cell, but not epithelial cell, function as a consequence of the loss of CD248. Taken together these studies suggest that CD248 represents a novel stromal cell specific target for the treatment of chronic kidney disease.

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Tyra, Paula Marie [Verfasser], Jürgen [Akademischer Betreuer] Floege et Peter [Akademischer Betreuer] Boor. « Collagen expression in renal fibrosis / Paula Marie Tyra ; Jürgen Floege, Peter Boor ». Aachen : Universitätsbibliothek der RWTH Aachen, 2021. http://d-nb.info/1240390912/34.

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Konstas, Angelos Aristeidis. « The regulation and functional interaction of the epilethial sodium channel (ENaC) and renal potassium channels ». Thesis, University of Oxford, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249463.

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Magalhães, Andréa Olivares. « Papel do fósforo e do paratormônio na progressão da doença renal crônica ». Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/5/5148/tde-04042008-142314/.

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Introdução: Os mecanismos envolvidos na progressão da doença renal crônica (DRC) independentemente de sua etiologia, não estão totalmente esclarecidos. O controle do fósforo(P) sérico é uma meta essencial a ser alcançada no tratamento de pacientes com DRC. Inicialmente, a importância deste controle era atribuída a participação do P na patogênese do hiperparatireoidismo secundário. Atualmente sabe-se que a hiperfosfatemia aumenta a mortalidade desses pacientes. Distúrbios do metabolismo mineral participam da progressão da DRC, porém os mecanismos envolvidos na fisiopatologia, não foram esclarecidos. Objetivo: Avaliar o efeito isolado da sobrecarga de P e de diferentes concentrações de paratormônio (PTH) na progressão da doença renal em ratos urêmicos. Materiais e métodos: Ratos Wistar machos adultos foram submetidos à paratireoidectomia (PTX) e nefrectomia 5/6 (NX), a seguir implantamos mini bombas osmóticas com diferentes concentrações de PTH ou veículo. Realizamos 2 experimentos. Experimento 1: Animais que receberam dietas com diferentes conteúdos de P (1,2% ou 0,2% dieta rica e pobre respectivamente).Estes animais receberam infusão fisiológica de PTH (1-34 rat PTH 0,022/100g/h). No experimento 2, os animais receberam as mesmas dietas porém infusão elevada de PTH (1-34 rat PTH 0,11/100g/h). Os animais controles (grupo controle e sham) foram os mesmos para os dois experimentos. A alimentação dos animais foi controlada por pair feeding e a pressão arterial caudal (PAC) foi aferida semanalmente. Após 8 semanas os animais foram sacrificados.Creatinina corrigida por peso, P, cálcio,PTH e hematócrito foram analisados. No tecido renal quantificamos a fibrose intersticial (FI), esclerose glomerular(EG) e o número de células apoptóticas. Avaliamos, no tecido renal a expressão de ED-1, alfa-actina, angiotensina II e TGF-beta. Resultados: Animais NX que receberam infusão fisiológica de PTH e dieta rica em P desenvolveram mais FI, EG, e maior expressão de ED-1. Os animais que receberam infusão elevada de PTH apresentaram maiores níveis tensionais. Foi demonstrado uma correlação entre os marcadores inflamatórios (TGF-beta e Angio II) confirmando a associação entre estes fatores no processo de fibrogênese. O número de células apoptóticas foi maior nos grupos NX que receberam PTH em concentração elevada. Conclusão: Neste estudo, a sobrecarga de P atuou na progressão da DRC ativando principalmente vias inflamatórias e o excesso de PTH agiu piorando a hipertensão arterial.
Introduction: The mechanisms involved in the progression of chronic kidney disease (CKD), regardless of its etiology, have yet to be well elucidated. Serum phosphorus control is an essential target to be achieved in the treatment of patients with CKD. Initially, the importance of this control was attributed to the participation of phosphorus (P) in the pathogenesis of secondary hyperparathyroidism. It is currently known that hyperphosphatemia increases mortality in these patients. Disturbances of the mineral metabolism participate in the progression of CKD; however, the mechanisms involved in pathophysiology remain unclear. Objective: To evaluate the isolated effect of phosphorus overload and different PTH concentrations in the progression of kidney disease in uremic rats. Materials and methods: Adult male Wistar rats were submitted to parathyroidectomy and nephrectomy 5/6; subsequently, we implanted mini osmotic pumps with different concentrations of PTH or vehicle. We carried out 2 experiments. Experiment 1: Animals who received diets with different P contents (1.2% or 0.2% rich and poor diet, respectively). These animals received infusion of PTH solution (1-34 rat PTH 0.022/100g/h). In experiment 2, the animals received the same diets; however, with high PTH infusion (1-34 rat PTH 0.11/100g/h). Control animals (control group and sham) were the same for both experiments. Food intake of the animals was controlled by pair feeding, and caudal artery pressure (CAP) was measured weekly. After 8 weeks, the animals were sacrificed. Creatinine, phosphorus, calcium, PTH and hematocrit were analyzed. Interstitial fibrosis (IF), glomerular sclerosis (GS), and number of apoptotic cells were quantified in the renal tissue. ED-1 expression, alfa-actin, angiotensin II and TGF-beta were evaluated in the renal tissue, as well. Results: NX animals that received infusion of PTH solution and P-rich diet developed more IF and GS, and greater ED-1 expression. The animals that received high PTH infusion presented higher tensional levels. A correlation was demonstrated between inflammatory markers (TGF-beta and Angio II) confirming the association between these factors in the fibrogenesis process. The number of apoptotic cells was higher in NX groups that received PTH in high concentration. Conclusion: In this study, phosphorus overload acted in the progression of CKD activating inflammatory pathways; in addition, excess PTH worsened arterial hypertension.

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Stangenberg, Stefanie. « Fetal programming of chronic kidney disease and novel treatment targets of renal fibrosis ». Thesis, The University of Sydney, 2017. http://hdl.handle.net/2123/17744.

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The thesis spans the spectrum of causative and therapeutic aspects of chronic kidney disease (CKD), which is a significant and growing health burden. An adverse in utero environment is increasingly recognised to predispose to chronic diseases in adulthood. Maternal smoking remains the most common modifiable adverse in-utero exposure leading to low birth weight, which is strongly associated with CKD in later life. In order to investigate underlying mechanisms for such susceptibility, a mouse model of maternal smoke exposure was used and the offspring examined at different developmental milestones. Maternal smoke exposure led to lower birth weight and increased proteinuria at adulthood compared to control. From birth throughout adulthood smoke exposed offspring had increased levels of mitochondria-derived oxidative stress and increased mitochondrial DNA copy numbers. In addition, the kidneys of smoke exposed offspring demonstrated mitochondrial structural abnormalities at birth and adulthood along with a reduction in oxidative phosphorylation (OXPHOS) proteins, lysosome density and mitochondrial antioxidants. The development of mitochondrial alterations preceding the proteinuria may point towards its mechanistic role in fetal programming of CKD in response to maternal smoking. While it is desirable that these findings will translate into effective strategies of CKD prevention, the disease is frequently diagnosed when renal fibrosis has already developed. Thus, the second part of this thesis focused on therapy and explored whether lysyl oxidase-like 2 (LOXL2), an enzyme central to extracellular matrix modification (ECM), would be suitable as a novel treatment target. LOXL2 was increased in early renal fibrosis after unilateral ureteral obstruction and in a diabetic mouse model that mimics the development of chronic renal fibrosis. Inhibition of LOXL2 with a highly selective, small molecule inhibitor reduced markers of ECM deposition in the diabetic mouse model. Importantly, LOXL2 inhibition resulted in amelioration of proteinuria and glomerulosclerosis in the diabetic mice. It thus had a beneficial effect on preserving glomerular structure and function. We conclude that it may be a suitable therapeutic target in diabetic nephropathy and renal fibrosis of other aetiologies.

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Van, Der Hauwaert Cynthia. « Déterminants moléculaires de la néphrotoxicité induite par le tacrolimus après transplantation rénale ». Thesis, Lille 2, 2014. http://www.theses.fr/2014LIL2S033/document.

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Bien que le Tacrolimus soit un immunosuppresseur largement prescrit en transplantation rénale, ses effets néphrotoxiques limitent son utilisation. En effet, le Tacrolimus contribue au développement de lésions de fibrose interstitielle rénale et d’atrophie tubulaire à plus ou moins brève échéance. Parmi les mécanismes qui interviennent dans le processus de fibrogenèse, la transition épithélio-mésenchymateuse (TEM) a été évoquée. Dans ce processus, une cellule épithéliale polarisée perd l’expression de certains de ses marqueurs épithéliaux (E-cadhérine, cytokératine, β-caténine membranaire...) au profit d’un phénotype mésenchymateux (expression de marqueurs mésenchymateux tels que vimentine ou translocation nucléaire de la β-caténine, sécrétion de composants de la matrice extracellulaire). Ainsi, afin d’identifier des déterminants moléculaires de la néphrotoxicité induite par le Tacrolimus et d’évaluer la contribution du processus de TEM, plusieurs approches in vitro et in vivo ont été combinées.Tout d’abord, un modèle de culture primaire de cellules tubulaires proximales rénales (CTP), cibles privilégiées des xénobiotiques au niveau rénal a été développé à partir de pièces opératoires. Ce modèle a été caractérisé : analyse de la stabilité sur 5 passages, de l’expression de marqueurs épithéliaux proximaux et mésenchymateux, et de la résistance trans-épithéliale... De plus, la comparaison de la capacité métabolique des échantillons de tissu rénal sain à différents modèles cellulaires (HEK293, HK-2, CTP) nous a permis de montrer que les CTP est le modèle le plus pertinent. De plus, l’exposition de cellules rénales au Tacrolimus induit une modification du phénotype des cellules.De plus, le développement d’un modèle murin de néphrotoxicité induite par le Tacrolimus a été réalisé (exposition durant 28 jours à une dose de 1 mg/kg/j de Tacrolimus par implantation sous-cutanée de pompes Alzet® ou par injection intra-péritonéale). Les données histologiques et d’expression génique montrent que les reins de souris traitées par Tacrolimus présentent des zones localisées d’expression des marqueurs mésenchymateux (vimentine) et de fibrose (collagène, α-SMA, miR-21). Par ailleurs, la variabilité interindividuelle des effets néphrotoxiques du Tacrolimus étant potentiellement associée à la présence de polymorphismes génétiques (SNP), les ADN de patients transplantés rénaux et de leur greffon ont été génotypés pour des SNP (i) affectant les CYP3A5 et ABCB1, intervenant dans la prise en charge du Tacrolimus, (ii) affectant la cavéoline-1, impliquée dans le processus de fibrose. Nos résultats montrent que deux SNP affectant le donneur (CYP3A5 6986A>G et ABCB1 3435C>T) sont significativement associés à une plus faible expression des marqueurs de TEM (expression de novo de la vimentine et translocation nucléaire de la β-caténine) et à un nombre moins important de lésions de fibrose rénale sur les biopsies de greffons à 3 mois post-greffe. Enfin, les patients porteurs d’un greffon de génotype CAV1 rs4730751AA ont une perte de fonction rénale plus rapide. Ces patients semblent développer plus fréquemment des lésions de fibrose. Dans le cadre de la transplantation rénale, ces résultats suggèrent que certains SNP du donneur influencent la néphrotoxicité du Tacrolimus et que son métabolisme in situ est un élément clé dans la compréhension de la fibrogenèse du greffon.Au total, les résultats obtenus nous ont permis d’identifier des facteurs individuels de vulnérabilité à la toxicité du Tacrolimus. De telles données, utilisées comme outil prédictif d’une néphrotoxicité plus ou moins importante, aideraient à un meilleur choix de traitement immunosuppresseur. A terme, sur le plan médico-économique, notre étude pourrait permettre d’améliorer la prise en charge de la néphrotoxicité des immunosuppresseurs, et ainsi réduire les coûts de traitement liés aux pertes de greffons induites par la toxicité du Tacrolimus
Although widely prescribed in kidney transplantation, Tacrolimus use is limited by its nephrotoxic effects. Indeed, Tacrolimus contributes to the development of renal interstitial fibrosis lesions and tubular atrophy with a large variability between patients. Among the mechanisms involved in fibrogenesis, the epithelial-mesenchymal transition (EMT) has been proposed. EMT is a dynamic process by which a polarized epithelial cell loses its epithelial markers (E-cadherin, cytokeratin, membrane β-catenin...) and acquires a mesenchymal phenotype (de novo expression of vimentin or nuclear translocation of β-catenin, secretion of extracellular matrix components). Thus, to identify molecular determinants of Tacrolimus-induced nephrotoxicity and to evaluate the contribution of EMT, several in vitro and in vivo approaches were combined.First, a model of primary culture of renal proximal tubular cells (PT cells), the main target of xenobiotics in kidney, has been developed and characterized: phenotypic stability, functional properties, expression of proximal and mesenchymal markers and transepithelial resistance. In addition, the comparison of the metabolic capacity of the healthy renal tissue samples to different cell models (HEK293, HK-2 CTP) has revealed that PT cells is the most appropriate model. Furthermore, renal cells exposure to Tacrolimus induced a modification of the cell phenotype.Moreover, the development of a murine model of Tacrolimus-induced nephrotoxicity has been performed (28 days-exposure at 1 mg/kg/day by subcutaneous implantation of Alzet® pumps or by intra-peritoneal injection). Histological and gene expression data indicated that kidney of Tacrolimus-treated mice exhibited localized expression of mesenchymal markers (vimentin) and fibrosis areas (collagen, α-SMA, miR-21).Furthermore, as the interindividual variability of Tacrolimus nephrotoxic effects is potentially associated with genetic polymorphisms (SNPs), renal transplant recipients and their corresponding graft were genotyped for (i) CYP3A5 and ABCB1 SNPs, involved in Tacrolimus cellular processing, (ii) caveolin-1 SNP, involved in fibrosis. Our results showed that two SNPs affecting the donor (CYP3A5 6986A> G and ABCB1 3435C> T) were significantly associated with a lower expression of EMT markers (vimentine de novo expression and nuclear translocation of β-catenin) together with less fibrosis lesions evaluated on renal graft biopsies performed at 3 months post-transplant. Finally, patients with a CAV1 rs4730751AA graft displayed a more severe renal function decrease. These patients also developed more frequently fibrotic lesions. In the context of renal transplantation, these results suggest that some donor SNPs modulate Tacrolimus-induced nephrotoxicity and that its in situ metabolism is a key element in the graft fibrogenesis understanding.Overall, these data allowed us to identify some molecular determinants of Tacrolimus-induced nephrotoxicity. Early identification of patients at high risk of Tacrolimus renal toxicity represents one of the most important and future challenges in kidney transplantation to tailor treatment before the development of irreversible lesions. Although preliminary, our data suggest that the genetic make-up of donors as well as the early detection of nephrotoxicity markers such as mesenchymal markers, may improve to the medical management of renal transplant patients

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Souza, Maysa Lucena de. « Expressão intra-renal dos RNA mensageiros de proteínas associadas ao podócito e de fatores pro fibróticos em glomerulopatias primárias e secundárias ». reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2015. http://hdl.handle.net/10183/139755.

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Introdução: A podocitopenia e a podocitúria são marcadores de injúria glomerular em podocitopatias (POD) e glomerulonefrites proliferativas (GNsP), e mesmo em fases iniciais destas doenças mecanismos pró-fibróticos indutores de glomeruloesclerose e fibrose renal progressiva estão ativados. Objetivo: Avaliar pacientes portadores de glomerulopatias biopsiados em diferentes tempos de evolução clínica, correlacionando lesões morfológicas dos compartimentos glomerular e túbulo-intersticial com a expressão dos RNAm de proteínas associadas ao podócito e de fatores pró-fibróticos no tecido renal. Materiais e Métodos: Foram incluídos no estudo oitenta e quatro pacientes adultos portadores de glomerulopatias de diferentes etiologias submetidos à biópsia renal por indicação clínica. As lesões histológicas foram individualizadas e a porcentagem de fibrose intersticial e atrofia tubular foi quantificada na coloração de Tricrômio de Masson. Foram mensurados no tecido renal o log 10 do RNAm pela reação em cadeia da polimerase em tempo real das proteínas associadas ao podócito alfa actinina-4, podocina e podocalixina e dos fatores pró-fibróticos fator de crescimento transformador ₁ (TGF₁), fator de crescimento do tecido conectivo (CTGF) e fator de crescimento derivado do endotélio A (VEGF-A). A secção livre de neoplasia de rins removidos por câncer renal foram usados como controles da expressão dos RNAm. Resultados: No grupo POD, os diagnósticos histopatológicos foram: Glomeruloesclerose segmentar e focal (n=20), GN membranosa (n=12), Nefropatia diabética (n=9) e Lesões mínimas (n=7); no grupo GNsP foram Nefropatia por IgA (n=15), GN membranoproliferativa (n=5), Nefrite lúpica (n=5) e GN proliferativa mesangial (n=4), e outros diagnósticos (n=7). O RNAm do tecido renal nos pacientes com POD e GNsP foi significativamente menor comparado ao dos controles para todos os genes estudados. A presença de crescentes, independente do estágio evolutivo, foi associada à maior expressão do RNAm de alfa actinina-4 (p=0,04), podocina (p=0,01) e podocalixina (p=0,038). O RNAm dos genes pró-fibróticos também estava inibido comparado a sua expressão no rim normal. Nas GNsP, o VEGF-A (p<0,001) e o CTGF (p<0,001) foram os genes com menor nível de expressão comparado aos controles. Em relação às biópsias com lesões crescênticas, tanto o RNAm do TGFβ1 (p=0,001) como do CTGF (p=0,041) tiveram maior expressão comparado ao RNAm das biópsias sem crescentes. Nas biópsias com fibrose intersticial superior a 30%, a expressão do RNAm de TGFβ1, (p=0,038) e do VEGF-A (p=0,040) foi maior do que nas biópsias com fibrose leve. O maior tempo entre o início da doença clínica e a realização da biópsia renal não teve influência detectável na expressão tecidual do RNAm dos biomarcadores estudados. Conclusões: Pacientes com podocitopatias ou glomerulonefrites proliferativas apresentaram inibição da expressão do RNAm de proteínas associadas ao podócito e de fatores indutores de fibrose renal, achados compatíveis com injúria podocitária e podocitopenia. Nas biópsias renais com maior grau de fibrose intersticial e atrofia tubular, assim também como naquelas com lesões crescênticas, a expressão do RNAm de fatores fibrogênicos como TGF-β1 e CTGF foi significativamente aumentada, o que pode sugerir supra-regulação de moléculas associadas a mecanismos de fibrose renal e patologia glomerular.
Introduction: Both podocitopenia and podocyturia are markers of glomerular injury in podocytopathies (POD) and proliferative glomerulonephritis (PGNs), and even in the early stages of these diseases pro-fibrotic mechanisms leading to glomerulosclerosis and progressive renal fibrosis are running. Objective: This study evaluated patients with glomerulopathies who were biopsied at different times of clinical evolution, correlating morphological lesions of the glomerular and tubulointerstitial compartments with renal messenger RNA (mRNA) expression of podocyteassociated proteins and pro-fibrotic factors. Materials and Methods: The study included eighty-four adult patients with glomerulopathies of different etiologies undergoing kidney biopsy as clinically indicated. The histological lesions were individualized and the percentage of interstitial fibrosis and tubular atrophy was quantified on Trichrome Masson staining. Tissue log 10 mRNA of the podocyte proteins alpha-actinin-4, podocin and podocalyxin and of the pro-fibrotic factors transforming growth factor β₁ (TGFβ₁), connective tissue growth factor (CTGF) and vascular endothelium growth factor A (VEGF-A) was measured by real time polymerase chain reaction. The sections free of neoplasia of kidneys removed for renal cancer were used as controls for the mRNA tissue expression. Results: Results: In the POD group, the histopathological diagnoses were: focal segmental glomerulosclerosis (n=20), membranous (n=12), diabetic nephropathy (n=9) and minimal changes (n=7); in PGNs group were IgA nephropathy (n=15), membranoproliferative (n=5), lupus nephritis (n=5) and mesangial proliferative (n=4), and other diagnoses (n=7). Messenger RNA expression of POD and PGNs groups was significantly lower compared to controls for all the studied genes. The presence of crescents, regardless of their evolutive stage, was associated with higher mRNA expression of alpha-actinin-4 (p=0.04), podocin (p=0.01) and podocalyxin (p=0.038). The mRNA of pro-fibrotic genes was also inhibited compared to their expression in normal kidneys. In PGNs, VEGF-A (p<0.001) and CTGF (p<0.001) were the genes with lowest mRNA levels compared to controls. Regarding the biopsies with crescentic lesions, both the mRNA of TGFβ1 (p=0.001) and CTGF (p=0.041) were highly expressed as compared to those of biopsies without crescents. In biopsies with moderate to severe interstitial fibrosis (more than 30%), the mRNA expression of TGFβ1 (p=0.038) and VEGF-A (p=0.040) was highly expressed compared to biopsies with mild fibrosis. A longer interval between the clinical disease and the performance of kidney biopsy did not have a detectable influence on tissue mRNA expression of the studied biomarkers. Conclusions: Patients with POD or PGNs presented inhibition of the mRNA expression of podocyte-associated proteins and pro-fibrotic factors, findings that are consistent with podocyte injury and podocitopenia. In renal biopsies with a higher degree of interstitial fibrosis and tubular atrophy, as well as those with crescentic lesions, the mRNA expression of fibrogenic factors such as TGF-β1 and CTGF was significantly increased, which may suggest upregulation of molecules associated with mechanisms of renal fibrosis and glomerular pathology.

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Goto, Yasufumi. « Studies on the molecular pathogenesis mechanism for renal fibrosis in hereditary nephrotic mouse ». Kyoto University, 2006. http://hdl.handle.net/2433/144093.

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Kyoto University (京都大学)
0048
新制・課程博士
博士(農学)
甲第12356号
農博第1537号
新制||農||923(附属図書館)
学位論文||H18||N4114(農学部図書室)
24192
UT51-2006-J348
京都大学大学院農学研究科応用生物科学専攻
(主査)教授久米新一, 教授矢野秀雄, 教授今井裕
学位規則第4条第1項該当

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Yang, Fuye. « Mechanisms of angiotensin II-induced renal fibrosis role of TGF-?SMAD signaling pathway / ». Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B42841641.

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Fretellier, Nathalie. « Rôle des complexes de gadolinium dans le mécanisme de la fibrose systémique néphrogénique ». Phd thesis, Université René Descartes - Paris V, 2013. http://tel.archives-ouvertes.fr/tel-00843108.

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La fibrose systémique néphrogénique (FSN) est une maladie rare et relativement récente, observée uniquement chez des patients souffrant d'insuffisance rénale sévère ou terminale. Elle est liée à l'administration d'une certaine catégorie de complexes de gadolinium (CG), les CGs thermodynamiquement moins stables, utilisés comme produits de contraste pour l'imagerie par résonance magnétique. L'hypothèse mécanistique la plus couramment citée concerne les effets profibrosants du Gd3+ " libre " après dissociation in vivo des CGs les moins stables mais il n'en existe pas de démonstration formelle. La physiopathologie de cette maladie reste mal connue, notamment par manque de modèles précliniques pertinents. Les travaux de cette thèse répondent donc à la nécessité d'approfondir nos connaissances concernant les relations entre les propriétés physicochimiques des CGs (structure, stabilité) et le risque de toxicité chronique, afin de mieux comprendre leur rôle dans le mécanisme de la FSN. Nous avons mis aux points plusieurs modèles de FSN chez le Rat. Nous avons aussi comparé les effets de toutes les catégories structurales des CGs sur ces modèles. Une toxicité systémique importante et la survenue de lésions cutanées macroscopiques et d'une fibrose du derme sont notées après administration de gadodiamide (un CG linéaire et ionique de faible stabilité), ce qui est cohérent avec le fait que la grande majorité des cas de FSN sont associés à cet agent. Nous avons aussi montré que cette toxicité dépend du degré d'insuffisance rénale et que l'hyperphosphatémie sensibilise les animaux aux effets profibrosants du gadodiamide. Nos données suggèrent donc que ces facteurs associés sont des facteurs de risque de la FSN. Nous avons observé la dissociation progressive in vivo de deux CGs linéaires présentant une faible stabilité, le gadodiamide et l'acide gadopentétique, après administration chez le Rat insuffisant rénal, avec libération de Gd3+ sous forme libre et soluble. Les CGs macrocycliques sont restés stables. Nous avons confirmé cette stabilité sur du sérum de Rat et du sérum humain alors que le gadodiamide se dissocie in vitro. Nos données suggèrent aussi une interaction entre l'ion Gd3+ dissocié à partir du gadodiamide et les protéines sériques. Cette libération de Gd3+ est accélérée en présence d'une forte concentration de phosphate. Globalement, nos résultats suggèrent ainsi un rôle causal du Gd3+ libre dans les lésions cutanées observées chez les animaux insuffisants rénaux. Enfin, nous avons observé l'implication de la voie de signalisation canonique de TGFβ, le marqueur clé de la fibrose, uniquement chez des rats ayant reçu le gadodiamide et dont l'insuffisance rénale est modérée. Nos travaux sont donc en faveur de l'hypothèse mécanistique d'une dissociation des CGs peu stables.

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Haller, Steven T. « Marinobufagenin Induced Uremic Cardiomyopathy : The Role of Passive Immunization, Rapamycin, and CD40 Signaling in The Generation of Renal Fibrosis ». University of Toledo Health Science Campus / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=mco1339092544.

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Semedo, Patricia [UNIFESP]. « O papel das células-tronco mesenquimais em modelos experimentais de doença renal aguda e crônica ». Universidade Federal de São Paulo (UNIFESP), 2009. http://repositorio.unifesp.br/handle/11600/9858.

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Fundação de Amparo à Pesquisa do Estado de São Paulo – FAPESP
Desde a década de 70 até o presente momento, o conhecimento sobre células-tronco (CTs) vêm crescendo exponencialmente. Dentre as CTs, interesse crescimento se dá no campo das células-tronco adultas, com especial atenção para as CTs da medula óssea, as células-tronco mesenquimais (CTMs). Muito têm se descoberto sobre o potencial terapêutico das CTMs para diversas patologias, devido a seu grande potencial em reparar tecidos e diminuir a inflamação local. Na área da nefrologia, muitos avanços foram feitos em doenças renais agudas e crônicas, entretanto as taxas de morbi-mortalidade mantêm-se elevadas. Devido ao caráter devastador das doenças renais, estudar uma forma alternativa de tratá-la está na terapia por CTMs. Nesse estudo, buscamos compreender o papel das CTMs em modelos renais agudo e crônico. Para tanto, em um modelo agudo de lesão de isquemia e reperfusão, CTMs foram administradas após 6h de reperfusão e analisadas em 24h e 48h. Os níveis de creatinina e uréia séricos apresentaram-se bem menores em 24h e 48h após reperfusão nos animais tratados com CTMs. Histologicamente, esses dados refletem em menor NTA e maior regeneração. Sabendo do potencial imunomodulador das CTMs, analisamos o perfil de citocinas no tecido renal. Observamos uma diminuição de citocinas inflamatórias (Th1) e aumento de citocinas anti-inflamatórias (Th2). Uma vez que realizamos o modelo experimental em ratos Wistar fêmeas e injetamos CTMs de machos, procuramos a CTM no tecido renal por PCR através da expressão do gene SRY (sex determing region Y). Em 24h, não encontramos as CTMs no tecido renal. Sistemicamente, a administração de CTMs exógenas não altera o perfil de citocinas Th1, porém leva ao aumento de citocinas Th2. Como os resultados foram animadores no modelo agudo, partimos para analisar o papel das CTMs no modelo renal crônico de nefrectomia 5/6. Com um tratamento contínuo de CTMs (a cada 2 semanas), após 8 semanas, observamos melhora nos níveis de creatinina e uréia sérica, bem como diminuição nos níveis de proteinúria. Apesar de uma tendência a melhorar o clearance de inulina nos animais tratados com CTMs, não houve diferença estatística com o grupo não tratado. Ao analisar a fibrose característica do modelo de 5/6, observamos menores índices de áreas fibróticas e glomerulosclerose no tecido dos animais tratados com CTMs, bem como redução em diversas moléculas fibróticas tais como Vimentina, Colágeno 1, TGF -β, FSP-1, Smad 3, MCP-1 e razão TIMP-1/MMP9. Já nesse modelo, as CTMs encontravam-se no tecido renal, e podemos correlacionar sua presença com o aumento de moléculas anti-fibróticas, tais como HO-1 e HGF. Em relação as citocinas expressas no tecido renal, novamente observamos uma polarização para citocinas Th2, o que por sua vez pode levar a inibição do processo de transição epitélio-mesenquimal (TEM). Surpreendentemente, a administração de CTMs levou a uma menor expressão de diversas citocinas séricas. Nos dois modelos utilizados, percebemos que administração de CTMs leva a melhora funcional renal, sendo o provável mecanismo envolvido nessa melhora a imunomodulação decorrente do tratamento, tanto no tecido renal quanto sistêmica, além da secreção de outras moléculas tais como HO-1 e HGF que medeiam processos anti-fibróticos, remodelando o tecido renal.
FAPESP: 06/0620-5
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Yang, Fuye, et 扬付叶. « Mechanisms of angiotensin II-induced renal fibrosis : role of TGF-{221}/SMAD signaling pathway ». Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B42841641.

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Thèses sur le sujet « Fibrosi renale »

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