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Dissertations / Theses on the topic 'Tubular epithelial cell'

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Published: 5 April 2025

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1

Neumann, Marc. "Epithelial cell rearrangements during tubular organ formation /." [S.l.] : [s.n.], 2005. http://edoc.unibas.ch/diss/DissB_7371.

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2

Kipari, Tiina Marika Johanna. "Inflammatory macrophages and renal tubular epithelial cell apoptosis." Thesis, University of Edinburgh, 2008. http://hdl.handle.net/1842/29197.

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Macrophages play a key role in renal inflammation and may be cytotoxic to resident cells within tissues. I begin this thesis by examining the effect of macrophages upon the level of apoptosis and proliferation in tubular epithelial cells in vitro. I then went on to examine the role of NO in vivo in the murine model of unilateral ureteric obstruction (UUO) characterised by tubular cell apoptosis and interstitial fibrosis. The specific iNOS inhibitor L-NIL (control D-NIL) was administered between days 5 to 7 following UUO. Mice were sacrificed at day 7 and the obstructed kidney removed for histological analysis. L-NIL treatment did not affect macrophage infiltration but did reduce both tubular and interstitial cell apoptosis. Proliferation of tubular cells and interstitial cells was unaffected. Interstitial fibrosis was significantly increased by L-NIL treatment. I also investigated the effect of conditional macrophage ablation in the UUO model. The conditional macrophage ablation mice used in these studies are transgenic for the human diphtheria toxin receptor (DTR) under the CD11b promoter (CD11b-DTR mice). Intraperitoneal (IP) administration of diphtheria toxin (DT) to DTR mice results in the rapid and specific depletion of monocytes and macrophages. DTR mice underwent UUO at day 0 and either DT or PBS was administered IP on days 5, 6 and 7. Mice were sacrificed at day 7 and the obstructed kidney removed for histological analysis. Administration of DT resulted in a 3-fold reduction in interstitial macrophage accumulation in obstructed kidneys. However, macrophage depletion had no effect upon proximal or distal tubular cell proliferation or apoptosis. Interestingly, macrophage depletion had no effect upon the accumulation of myofibroblasts but attenuated interstitial fibrosis.
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3

Tang, Chi-wai Sydney, and 鄧智偉. "The many facets of the renal proximal tubular epithelial cell inhuman." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B31992468.

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4

Tang, Chi-wai Sydney. "The many facets of the renal proximal tubular epithelial cell in human." Click to view the E-thesis via HKUTO, 2005. http://sunzi.lib.hku.hk/hkuto/record/B31992468.

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5

Meimaridou, Eirini. "Calcium oxalate modulation of tubular epithelial cell mitochondria : oxidative vulnerability due to restricted glutathione homeostasis." Thesis, University College London (University of London), 2007. http://discovery.ucl.ac.uk/1444828/.

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Calcium oxalate (COM) crystals are the commonest component of kidney stones. These arise mainly in the distal tubules and collecting ducts. To gain further insight for the cellular damage in terms of oxidative stress caused by COM deposition, in vitro and in vivo model studies were performed. In vitro In renal distal tubule cells, COM and free oxalate treatment caused a 3- and 2-fold increase respectively in superoxide (O2*") formation, originating from mitochondria. This was measured by lucigenin chemiluminescence in digitonin permeabilised cells. However, hydroxyapatite produced a much lower but significant enhancement of 02*", whilst other micro-particles, uric acid crystals, brushite, zymosan, and latex beads had no effect. When EDTA was omitted during O2*" monitoring, COM induced mitochondrial 02*" was ablated indicating a requirement for the release of free oxalate. Mitochondrial oxalate uptake was studied by employing different oxalate transport inhibitors. Omitting phosphate from the media or using mersalyl both of which block dicarboxylate transport, caused a significant decrease in the 02*" formation evoked by COM treatments. Using the membrane potential sensitive-probe tetramethylrhodamine methyl ester (TMRM) together with confocal microscopy, evidence is presented that in cells where COM binding had occurred a marked change in the mitochondrial membrane potential (Aij/m) occurred. COM also modulated intracellular Ca2+ signalling as demonstrated using the Ca2- sensitive dye Fura-2 AM, and this was via a non-mitochondrial mechanism. In Vivo Using a rat model of crystalluria and renal stones initiated by treatment with ethylene glycol (EG) and 1, 25-dihydroxycholecalciferol (DHC), nephrolithiasis arose in kidneys and this was linked to oxidative stress. In the EG + DHC treated animals where crystalluria was evident, this oxidative insult was manifest by a decrease in total and mitochondrial glutathione concentration, as well as an increased activity of glucose-6-phosphate dehydrogenase. Severe kidney damage at the mitochondria level was a further observation, indicated by the diminished O2 consumption resulting in a lowered O2 production. In addition, histopathological analysis revealed increased renal tubular pathology characterised by obstruction, distension and interstitial inflammation. The above findings were not observed in hyperoxaluria (EG) or calciuria (DHC) and are therefore a direct effect of crystal formation in kidney distal tubules that have implications in kidney stone disease which are discussed.
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6

Machiguchi, Toshihiko. "Cellular interactions via conditioned media induce in vivo nephron generation from tubular epithelial cells or mesenchymal stem cells." Kyoto University, 2014. http://hdl.handle.net/2433/189325.

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7

Ashman, Neil. "L-Arginine Transport and Metabolism in an In Vivo Model of Proteinuric Proximal Tubular Epithelial Cell Injury." Thesis, Queen Mary, University of London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.498591.

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8

Li, Moying [Verfasser], and Hans-Joachim [Akademischer Betreuer] Anders. "Mdm2 prevents spontaneous tubular epithelial cell death and acute kidney injury / Moying Li ; Betreuer: Hans-Joachim Anders." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/1186629444/34.

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9

Gallagher, Hugh. "Megalin, cubilin and the proximal tubular epithelial cell : extracellular and intracellular interactions and their relevance to the progression of chronic renal disease." Thesis, St George's, University of London, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.416020.

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10

Breda, Philippe Christophe [Verfasser]. "Renal proximal tubular epithelial cells exert immunomodulatory function by driving inflammatory CD4+ T cell responses : Renale proximale Tubulusepithelzellen üben durch Auslösen von inflammatorischen T-Zell-Antworten eine immunmodulatorische Funktion aus / Philippe Christophe Breda." Hamburg : Staats- und Universitätsbibliothek Hamburg Carl von Ossietzky, 2020. http://d-nb.info/1221276344/34.

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11

Ruscica, Biagina. "The critical role of YAP and TAZ in tubular homeostasis." Electronic Thesis or Diss., Université Paris Cité, 2024. https://wo.app.u-paris.fr/cgi-bin/WebObjects/TheseWeb.woa/wa/show?t=6623&f=77103.

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Des études épidémiologiques et expérimentales suggèrent que la progression de la maladie rénale chronique (MRC) après une lésion initiale est génétiquement déterminée, mais les réseaux génétiques qui contribuent à cette prédisposition restent inconnus. Parmi les voies moléculaires potentielles impliquées dans la MRC, cette étude s'est concentrée sur la voie Hippo, une cascade de signalisation conservée au cours de l'évolution et cruciale pour la régulation de la taille des organes et de la prolifération cellulaire. Les protéines paralogues YAP et TAZ, deux coactivateurs transcriptionnels de la voie Hippo, ont récemment été identifiées comme étant également des mécanosenseurs, capables de détecter un large éventail de signaux mécaniques et de les traduire en programmes transcriptionnels spécifiques aux cellules. L'activation de YAP et TAZ a été impliquée dans la progression de plusieurs maladies rénales et dans la transition de la lésion rénale aiguë (LRA) à la MRC . Cependant, les mécanismes sous-jacents restent obscurs et leur rôle dans des conditions physiologiques n'est pas encore bien compris. L'objectif de ce projet est d'élucider le rôle de YAP et TAZ dans les tubules rénaux. Tout d'abord, en utilisant la combinaison de modèles de souris transgéniques et de néphrectomie comme modèle de MRC, nous avons étudié l'effet de l'inactivation sélective du gène Yap ou Taz dans les cellules tubulaires rénales dans ce contexte de maladie. Nos résultats ont révélé une redondance potentielle entre ces deux protéines dans les cellules épithéliales tubulaires. Il est intéressant de noter que nos souris déficientes à la fois en YAP et en TAZ ont développé spontanément un phénotype rénal sévère avec des lésions tubulaires, de la fibrose et de l'inflammation, qui a été décrit en détail dans ce travail. Grâce à l'analyse transcriptomique, nous avons identifié une nouvelle signature moléculaire qui pourrait permettre de mieux comprendre les mécanismes régulés par YAP et TAZ dans les cellules tubulaires. Paradoxalement, dans notre modèle de double knock-out, nous avons observé une aggravation de l'expression et de l'activation de YAP et TAZ, parallèlement à la progression des lésions. Ceci semble être le résultat d'une expansion des cellules « non recombinées », montrant les rôles complexes de YAP et TAZ dans la communication avec les cellules voisines. Ces données démontrent le rôle essentiel de YAP et TAZ dans le maintien de l'homéostasie tubulaire et l'équilibre complexe nécessaire à leur régulation. Cette complexité peut avoir des implications pour les stratégies thérapeutiques ciblant l'inhibition de YAP et TAZ dans les maladies rénales, surtout si l'on considère les effets secondaires potentiels qui pourraient rendre ces approches plus difficiles
Epidemiological and experimental studies suggest that the progression of Chronic Kidney Disease (CKD) after an initial injury is genetically determined, but the genetic networks that contribute to this predisposition remain unknown. Among the potential molecular pathways involved in CKD, this study focused on the Hippo pathway, an evolutionarily conserved signaling cascade crucial for regulating organ size and cell proliferation. The paralogs proteins YAP and TAZ, two transcriptional coactivators of the Hippo pathway, have recently been identified also as mechanosensors, capable of detecting a wide range of mechanical cues and translating them into cell-specific transcriptional programs. Activation of YAP and TAZ has been implicated to the progression of several kidney diseases and in the transition from acute kidney injury (AKI) to CKD. However, the underlying mechanisms remain unclear and their role under physiological conditions is still not well understood. The aim of this project is to elucidate the role of YAP and TAZ in the renal tubules. First, using the combination of inducing transgenic mouse models and nephrectomy as a model of CKD, we investigated the effect of the selective inactivation of Yap or Taz gene in renal tubular cells in this disease context. Our findings revealed a potential redundancy between these two proteins in tubular epithelial cells. Interestingly, our mice deficient in both YAP and TAZ developed a spontaneous severe renal phenotype with tubular injury, fibrosis and inflammation, which was described in detail in this work. Through transcriptomic analysis, we identified a new novel molecular signature that may provide further insight into the mechanisms regulated by YAP and TAZ in tubular cells. Paradoxically, in our double knock-out model, we observed a worsening of YAP and TAZ expression and activation, in parallel with the lesion progression. This appeared to be the result of an expansion of the "non-recombined" cells, showing the complex roles of YAP and TAZ in the cross-talk with the neighbouring cells. These data demonstrated the essential role of YAP and TAZ in maintaining tubular homeostasis and the intricate balance required for their regulation. This complexity may have implications for therapeutic strategies targeting the inhibition of YAP and TAZ in kidney disease, especially considering the potential side effects that could make such approaches more challenging
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12

Sampangi, Sandeep. "Autologous human kidney proximal tubule epithelial cells (PTEC) modulate dendritic cell (DC), T cell and B cell responses." Thesis, Queensland University of Technology, 2015. https://eprints.qut.edu.au/82033/1/Sandeep_Sampangi_Thesis.pdf.

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This is a comprehensive study of human kidney proximal tubular epithelial cells (PTEC) which are known to respond to and mediate the pathological process of a range of kidney diseases. It identifies various molecules expressed by PTEC and how these molecules participate in down-regulating the inflammatory process, thereby highlighting the clinical potential of these molecules to treat various kidney diseases. In the disease state, PTEC gain the ability to regulate the immune cell responses present within the interstitium. This down-regulation is a complex interaction of contact dependent/independent mechanisms involving various immuno-regulatory molecules including PD-L1, sHLA-G and IDO. The overall outcome of this down-regulation is suppressed DC maturation, decreased number of antibody producing B cells and low T cell responses. These manifestations within a clinical setting are expected to dampen the ongoing inflammation, preventing the damage caused to the kidney tissue.
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13

Bozić, Stanojević Milica. "Glutamatergic signaling in proximal tubular cells maintains the epithelial phenotype and decreases epithelial-mesenchymal transition." Doctoral thesis, Universitat de Lleida, 2011. http://hdl.handle.net/10803/51013.

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14

Chou, Che-Yi. "The mechanism of transglutaminase 2 externalisation in renal tubular epithelial cells." Thesis, University of Sheffield, 2011. http://etheses.whiterose.ac.uk/2773/.

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Transglutaminase type 2 (TG2) catalyses the formation of an ε-(γ-glutamyl)-lysine isopeptide bonds between adjacent peptides or proteins including those of the extracellular matrix(ECM). ECM crosslinking has been associated with both the acceleration of collagen deposition while conferring the ECM with resistance to proteolytic degradation. Subsequently the cellular secretion of TG2 has been associated with wound healing and aberrant wound healing leading to kidney, lung, liver and heart fibrosis as well as atherosclerosis. TG2 has no signal peptide and cannot be transported classically. It is unknown how TG2 is targeted to the cell surface and secreted into ECM. Understanding TG2 transport may help to develop specific mechanisms to interfere with TG2 action in the scarring process. In this study, we identified that amino acids 88-106 in N-terminal β-sandwich domain of TG2 molecule is crucial for TG2 externalisation using deletion and mutation analysis in three renal tubular epithelial cells (TEC). Of interest, this TG2 export motif (aa88-106) itself appeared to be able to target other proteins for extracellular secretion. Yeast-two-hybrid studies were then performed to identify what the TG2 export motif would bind to and thus give clues as to the downstream mechanism of trafficking. Large T antigen (LTA) and tapasin were identified as binding partners. The interaction between LTA or tapasin and TG2 was confirmed by co-immunoprecipitation using endogenous protein from wild-type cells. TG2 externalisation was significantly decreased when LTA and tapasin were knockdown using siRNA suggesting that large T antigen and tapasin is involved in TG2 externalisation process. The possible TG2 externalisation pathway was explored further using fluorescent imaging including co-localisation analysis and live cell imaging. TG2 was predominantly co-localised with endoplasmic reticulum (ER) around the cell nucleus, but not localised with Golgi apparatus and lysosomes. We observed plasma membrane blebbing in the cells transfected with wild-type TG2 but not in the cells transfected withTG2 carrying a mutation in the export motif. Plasma membrane blebbing or a direct molecular trap is the most likely mechanism for TG2 externalisation based on the data generated. In conclusion, the amino acid sequence 88-106 in β-sandwich domain of TG2 is critical to TG2 externalisation in TEC. This export motif binds to large T antigen and tapasin. Large T antigen and tapasin is involved in TG2 externalisation possibly through plasma membrane blebbing or direct molecular trap in TEC.
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15

Orphanides, Chrystalla. "Hypoxia is a pro-fibrogenic stimulus for human renal tubular epithelial cells." Thesis, University College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.314192.

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16

Ho, Sau-kwan, and 何秀鈞. "Interactions of anti-dsDNA antibodies with human proximal renal tubular epithelial cells in the pathogenesis of lupus nephritis." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/197161.

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Lupus nephritis is characterized by the production of anti-dsDNA antibodies, deposition of immune complexes within the kidney parenchyma, proliferation of resident renal cells and induction of inflammatory and fibrotic processes. Approximately 70% of patients with lupus nephritis show immune aggregates along the tubular basement membrane, which is accompanied by an influx of infiltrating cells and increased intra-renal expression of IL-6. Much attention has focused on the inflammatory processes in the kidney during pathogenesis of lupus nephritis whereas mechanisms of fibrogenesis are less well characterized. Tubulo-interstitial injury is a key indicator of poor prognosis of renal function. Given that the tubulo-interstitium occupies over 80% of the kidney volume, injury to this compartment will have a major impact on renal function. There is evidence to show that proximal tubular epithelial cells (PTEC) undergo epithelial-to-mesenchymal transition (EMT) during pathological disorders and adopt a fibroblastic morphology with increased fibrogenic potential. We have previously demonstrated that anti-dsDNA antibodies bound directly to the surface of PTEC through cross-reactive proteins, which were subsequently internalized and translocated to the nucleus where they induced functional changes. Using a proteomic approach, this study identified the cross-reactive antigens that mediated anti-dsDNA antibody binding and intracellular localization in PTEC and the functional consequences thereafter, focusing on EMT and fibrogenic events. Human polyclonal anti-dsDNA antibodies isolated from patients with lupus nephritis bound to Ku70 in plasma membrane extracts isolated from PTEC, and to Ku70, Ku80 and major vault protein in cytosolic and nuclear fractions. Anti-dsDNA antibodies increased synthesis of Ku70, Ku80 and major vault protein in PTEC in a time-dependent manner. Expression of these proteins was localized to proximal tubules especially those undergoing atrophy, and staining was more prominent in renal biopsies from patients with lupus nephritis compared to non-lupus renal disease or control specimens. Binding of anti-dsDNA antibodies to PTEC increased phosphorylation of MAPK and PKC signaling pathways that was accompanied by a concomitant increase in IL-6, IL-8 and TGF-1 secretion and synthesis of β-catenin, fibroblast specific protein-1, fibronectin and laminin. Inhibition of MAPK and PKC signaling pathways with specific inhibitors revealed differential regulation of inflammatory and fibrotic processes by these signaling pathways. In this respect, increased ERK, p38 MAPK, JNK and PKC phosphorylation in PTEC following anti-dsDNA antibody stimulation enhanced IL-6, IL-8 and fibronectin synthesis, whereas increased ERK and JNK phosphorylation upregulated TGF-β1 secretion. Increased β-catenin synthesis was mediated through JNK and PKC phosphorylation. Taken together, our data suggest that PTEC contribute to the pathogenesis of renal inflammation and fibrosis in lupus nephritis. We hypothesize that anti-dsDNA antibodies bind to Ku70 on the plasma membrane of PTEC to mediate inflammation, cell activation and increased fibrogenesis. Although synthesis of EMT markers was increased in PTEC after anti-dsDNA antibody stimulation, transition to a fibroblastic morphology was not observed under our experimental setting suggesting that induction of the EMT cascade is an early event before phenotypic alterations.
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Medicine
Master
Master of Philosophy
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17

MacPherson, Matthew. "Calcium signalling in a fluid transporting epithelium." Thesis, University of Glasgow, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.341710.

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18

Luo, Dong-Dong. "Regulation of transforming growth factor beta-1 signalling in the renal proximal tubular epithelial cells." Thesis, Cardiff University, 2010. http://orca.cf.ac.uk/55488/.

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The data presented shows that IL-1beta has a biphasic effect on PTC TGF-beta signalling, with early NF-kappaB-mediated inhibition and delayed sensitization via an autocrine IL-6 loop, and possibly also via an autocrine IL-6 loop, and possibly also via a switch from NF Kappa B p52/p50 heterodimer to p50/p50 homodimer formation. Secondly, the data indicates that BMP-7 prevents TGF-beta1-mediated loss of the transcriptional repressor SnoN and hence specifically limits Smad3 DNA binding, altering the balance of transcriptional responses to TGF-beta1 in PTC.
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19

Lim, Ai Ing, and 林艾盈. "Shedding of kidney injury molecule-1 by kidney proximal tubular epithelial cells: the role of matrixmetalloproteinase-3." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B49799745.

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Regardless of the original cause and etiology, the progression of kidney disease follows a final common pathway associated with tubulointerstitial injury, in which proximal tubular epithelial cells (PTEC) are instrumental. Kidney injury molecule-1 (KIM-1) is an emerging biomarker of kidney tubular damage. It is markedly expressed and released into urine in various animal models and human kidney diseases. This study aimed to explore the underlying mechanism regulating the release of KIM-1 by PTEC. First, expression and release of KIM-1 by primary cultured human PTEC were examined. In quiescent PTEC, KIM-1 was detected at the plasma membrane and in the cytoplasm. A transwell system, in which PTEC were grown as monolayer on permeable membrane, was used to examine the polarized release of KIM-1. PTEC constitutively released KIM-1 from their apical surface, and the release was independent of gene expression or protein synthesis. The KIM-1 release process by PTEC was enhanced dose- and time-dependently by two important kidney injury mediators, human serum albumin (HSA) and tumor necrosis factor (TNF)-α, and was inhibited by the presence of broad-spectrum inhibitors of matrix metalloproteinases (MMP). Second, the potential sheddases responsible for KIM-1 shedding were identified by quantitative polymerase chain reaction (PCR) array system, in which the gene expression of a panel of MMP members was screened. The gene expression of MMP-3, MMP-7 and MMP-9 was up-regulated by PTEC under HSA or TNF-α activation. Blockade experiments with synthetic MMP inhibitors or MMP gene knockdown by small interfering RNA transfection, revealed that the constitutive or accelerated KIM-1 shedding was mediated by MMP-3, but not MMP-7 or MMP-9. The role of MMP-3 in KIM-1 shedding was further defined by additional data showing the enhanced MMP-3 synthesis by HSA- or TNF-α-stimulated PTEC, and the up-regulated KIM-1 shedding by PTEC following exogenous MMP-3 treatment. Third, the regulatory mechanism of MMP-3-mediated KIM-1 shedding was investigated. Treatment of PTEC with HSA or TNF-α up-regulated the reactive oxygen species (ROS) generation, and its kinetics ran parallel to the increase of KIM-1 shedding and MMP-3 synthesis. In addition, exogenous hydrogen peroxide dose-dependently induced KIM-1 shedding and MMP-3 synthesis, which were abolished by the presence of an oxidation inhibitor. These evidence suggest that ROS play an essential role in regulating the MMP-3-mediated KIM-1 shedding by PTEC. Finally, a mouse model of acute kidney injury induced by renal ischemia and reperfusion (I/R) was established to translate the in vitro findings. Reduced kidney function and increased urinary KIM-1 level were observed in mice after renal I/R treatment. Strikingly, the expression of MMP-3 and KIM-1 in the I/R treated mice was most profound in the S3 segments of the proximal tubules, where is the most susceptible area to oxidative stress. Taken together, these in vivo data have further strengthened the distinct roles of ROS and MMP-3 in KIM-1 shedding during PTEC injury. In conclusion, ROS generated by the injured PTEC activate MMP-3, which release the soluble KIM-1 through the ectodomain shedding process.
published_or_final_version
Medicine
Master
Master of Philosophy
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20

Asselman, Marino. "Hyaluronan biology and regulation in renal tubular epithelial cells and its role in kidney stone disease." [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 2008. http://hdl.handle.net/1765/13147.

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21

Selbi, Wisam Dhafer Rashid. "Regulation and function of hyaluronan in renal proximal tubule epithelial cells." Thesis, Cardiff University, 2006. http://orca.cf.ac.uk/54266/.

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v. HA binding proteins (Hyaladherins) differentially affected extracellular HA structures. Inter-alpha-trypsin inhibitor (loci) is important in the formation of HA coats as well as HA cables. Tumour necrosis factor-stimulated gene-6 (TSG-6) is seen to be crucial to the formation of HA coats but not HA cables, while the role of versican in either structures is not fully determined yet although it is thought to be more crucial to the formation of HA cables.
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22

Xiao, Jing. "Crosstalk between peroxisome proliferator-activated receptor-[gamma] and angiotensin II in renal proximal tubular epithelial cells in IgA nephropathy." Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B42182384.

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23

Afrin, Sadia. "Defining a 3-dimensional (3D) in vitro model to study immune cell and renal cell interactions." Thesis, Queensland University of Technology, 2015. https://eprints.qut.edu.au/84754/1/Sadia_Afrin_Thesis.pdf.

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This study aimed to develop a 3-Dimensional (D) hydrogel system for the co-culture of autologous human renal and immune cells. Previous studies have shown that human renal epithelial cells are able to modulate autologous immune cell responses. However, these studies were undertaken in a standard 2D culture system. The 3D model was developed to re-capitulate these observations within a more physiological relevant in vivo like environment.
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24

Xiao, Jing, and 肖婧. "Crosstalk between peroxisome proliferator-activated receptor-[gamma] and angiotensin II in renal proximal tubular epithelial cells in IgAnephropathy." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B42182384.

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25

Shah, Nileshkumar. "Expression and regulation of cadherin of human renal proximal tubule epithelial cells." Thesis, St George's, University of London, 2018. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.754076.

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Cadherins are a family of trans-membrane junctional proteins important in maintenance of cell-cell junction, phenotype regulation, tissue organisation and embryonic development. The proteins form calcium dependent homophilic cell junctional complexes and bind internally to the actin cytoskeleton and regulate intracellular signalling via the p- catenin pathway. Altered cadherin expression is essential for embryonic development, tissue repair or healing, fibrosis, cancer and metastasis. Much interest has developed in cadherin expression and its regulation along with signalling in renal proximal tubule epithelial cells (PTECs), an important cell type in the development of tubulointerstitial fibrosis and a potential source of myofibroblasts.
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26

Lee, Yin-yin Candice. "The role of thrombospondin-1 in the synthesis and activation of TGF-[beta]1 in human proximal tubular epithelial cells under elevated glucose concentrations /." View the Table of Contents & Abstract, 2005. http://sunzi.lib.hku.hk/hkuto/record/B31596010.

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27

Glynne, Paul Alexander. "The role of inducible nitric oxide synthase in renal proximal tubule epithelial cells." Thesis, Imperial College London, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.399540.

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28

Broadbelt, Nalini V. "Regulation of iNOS expression : in response to pressure in proximal tubule epithelial cells /." Access full-text from WCMC, 2008. http://proquest.umi.com/pqdweb?did=1619205731&sid=2&Fmt=2&clientId=8424&RQT=309&VName=PQD.

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29

Ng, Yee-ching Claudia. "Effects of anti-DNA antibodies and mycophenolic acid on inflammatory and fibrotic processes in proximal tubular epithelial cells and the implications in the pathogenesis of lupus nephritis." Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B43085234.

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30

Zhou, Li. "The molecular mechanisms of aristolochic acid nephropathy." Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B43224349.

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31

Lee, Yin-yin Candice, and 李嫣然. "The role of thrombospondin-1 in the synthesis and activation of TGF-{221}1 in human proximal tubular epithelial cells under elevatedglucose concentrations." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B45012829.

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32

Ng, Yee-ching Claudia, and 吳綺菁. "Effects of anti-DNA antibodies and mycophenolic acid on inflammatory and fibrotic processes in proximal tubular epithelial cells and theimplications in the pathogenesis of lupus nephritis." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B43085234.

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33

Pekalski, Marcin. "Renal allograft regjection : The role of TGFB in the differentiation on intragraft T cells and tubular epithelium." Thesis, University of Newcastle Upon Tyne, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.506537.

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34

Law, Becker M. P. "The functional characterisation of human innate lymphocytes in renal fibrosis and chronic kidney disease." Thesis, Queensland University of Technology, 2019. https://eprints.qut.edu.au/132513/1/Becker%20Meng-Po_Law_Thesis.pdf.

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This thesis by publication is a step forward in understanding the function of discrete immune cell populations in kidneys with chronic inflammation and fibrosis. We have successfully identified various human immune cells of the innate immune system as critical drivers of chronic kidney disease. The findings of this thesis sheds light on novel functions of innate immune cells and opens opportunities for the development of novel kidney therapies.
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35

Breggia, Anne C. "The JAK2/Y343/STAT 5 Signaling Axis is Required for Erythropoietin - Mediated Protection against Ischemic Injury in Renal Tubular Epithelial Cells." Fogler Library, University of Maine, 2008. http://www.library.umaine.edu/theses/pdf/BreggiaAC2008.pdf.

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36

Langford, Peter R. "c-Met Initiates Epithelial Scattering through Transient Calcium Influxes and NFAT-Dependent Gene Transcription." BYU ScholarsArchive, 2011. https://scholarsarchive.byu.edu/etd/3186.

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Hepatocyte growth factor (HGF) signaling drives epithelial cells to scatter by breaking cell-cell adhesions and migrating as solitary cells, a process that parallels epithelial-mesenchymal transition. HGF binds and activates the c-Met receptor tyrosine kinase, but downstream signaling required for scattering remains poorly defined. This study addresses this shortcoming in a number of ways.A high-throughput in vitro drug screen was employed to identify proteins necessary in this HGF-induced signaling. Cells were tested for reactivity to HGF stimulation in a Boyden chamber assay. This tactic yielded several small molecules that block HGF-induced scattering, including a calcium channel blocker. Patch clamping was used to determine the precise effect of HGF stimulation on Ca2+ signaling in MDCK II cells. Cell-attached patch clamping was employed to detect Ca2+ signaling patterns, and channel blockers were used in various combinations to deduce the identity of Ca2+ channels involved in EMT. The results of these experiments show that HGF stimulation results in sudden and transient increases in calcium channel influxes. These increases occur at predictable intervals and rely on proper tubulin polymerization to appear, as determined through the use of a tubulin polymerization inhibitor. Though multiple channels occur in the membranes of MDCK II cells, noticeably TRPV4 and TrpC6, it is TrpC6 that is specifically required for HGF-induced scattering. These HGF-induced calcium influxes through TrpC6 channels drive a transient increase in NFAT-dependent gene transcription which is required for HGF-induced EMT. This was determined through the use of luciferase-based NFAT reporter assays and confirmed through confocal immunofluorescence. Using a small-molecule inhibitor of WNK kinase, it was determined that loss of WNK kinase function is sufficient to prevent HGF-induced EMT. Furthermore, patch-clamp analysis demonstrated that WNK kinase significantly increases channel opening at the surface of MDCK cells, indicating a possible mechanism of action for c-Met inhibition, but leaving doubt as to whether WNK kinase is in fact normally involved in c-Met signaling, or whether it is simply permissive.
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37

Bommayya, Girish. "Role of tumour necrosis factor alpha stimulated Gene-6 in the regulation of peri-cellular hyaluronan assembly in renal proximal tubular epithelial cells." Thesis, Cardiff University, 2011. http://orca.cf.ac.uk/42055/.

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Epithelial mesenchymal transdifferentiation (EMT) has been shown to contribute to renal disease and tissue fibrosis and is known to be mediated by transforming growth factor-β (TGF-β). EMT involves loss of an epithelial phenotype and acquisition of a mesenchymal or myofibroblastic phenotype shown by up-regulation of α-smooth muscle actin (α-SMA). Assembly of hyaluronan (HA) has an important role in extracellular matrix formation and in maintaining the phenotype of different cells. HA has been shown to organize into cable structures or peri-cellular coats. Cable HA binds to inflammatory proteins and prevents their cell surface interaction and has anti-inflammatory properties, while peri-cellular coats make cells migratory. HA assembly is influenced by its interaction with hyaladherins and this study investigated the role of tumour necrosis factor-α stimulated gene (TSG)-6, one of the hyaladherins by assessing its interaction with HA, HABP and CD44 in proximal tubular cells (PTC) EMT. TSG-6 has an important role as an anti-inflammatory protein and is upregulated when stimulated with interleukin-1β (IL-1β) and TGF-β. In the presence of TGF-β, PTCs were demonstrated to be less migratory, with reduced E-cadherin and increased α-SMA expression suggesting TSG-6 may have important role in EMT. Both IL-1β and TGF-β induce increased expression of hyaluronan synthase (HAS) 2 and HA receptor, CD44. This also leads to loss of HA cables and increased assembly of an HA coat. Knockdown of TSG-6 gene in PTC leads to loss of HA cables and the peri-cellular assembly of HA coat was loose and scattered. These TSG-6 knockdown PTCs maintained its epithelial phenotype and TGF-β-mediated phenotypic transition was blocked. There was increased expression of CD44 and HAS2 in these TSG-6 knockdown cells and in subsequent experiments where CD44 was silenced with transfection, HAS2 expression was inhibited. This suggests that HAS2 expression was dependent on CD44 in the absence of TSG-6. These results collectively show that TSG-6 has an important role in EMT in PTCs.
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38

Diwakar, Ramaswamy. "The regulation of the actions of albumin in proximal tubular epithelial cells by endocytosis and the role played by adaptor protein disabled 2." Thesis, St George's, University of London, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.511902.

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39

Hovater, Michael. "Underlying purinergic signaling important for monocilium-dependent signaling in ductal epithelia : implications for polycystic kidney disease." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2006. http://www.mhsl.uab.edu/dt/2007m/hovater.pdf.

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40

Zhou, Li, and 周莉. "The molecular mechanisms of aristolochic acid nephropathy." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B43224349.

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41

Durkan, Anne Maria. "The expression of CX₃CL1 (fractalkine) in renal tubular epithelial cells and the regulation of CX₃CL1 by stimulation of the thromboxane prostanoid receptor." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/24546.

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Most renal diseases have a common end inflammatory pathway, which is associated with a leukocytic infiltrate. Chemokines are small proteins that are responsible for the chemoattraction of leukocytes into areas of injury or insult. CX3CL1, also known as fractalkine, exists as a transmembrane protein as well as a soluble protein. It acts as a cell adhesion molecule in addition to its chemoattractant properties. This thesis firstly examines the distribution of CX3CL1 in renal tubular epithelial cells (RTEC) and in the second part of the thesis the regulation of CX3CL1 by stimulation of the thromboxane prostanoid (TP) receptor is examined. The localisation of CX3CL1 was initially demonstrated primarily on the apical surface of tubular epithelial cells in human renal biopsy specimens with histological diagnoses of acute tubular necrosis and acute allograft rejection. A cell model was then developed in MDCK cells to examine the distribution more closely. There are a limited number of mechanisms potentially responsible for the trafficking of CX3CL1 to the apical membrane and it was established that N-glycosylation of CX3CL1 is required for its presence on the apical membrane of RTEC. The mobility of CX3CL1 within the cell membrane was next assessed and it was shown to be relatively immobile. We hypothesized that this would promote cell adhesion and indeed further experiments confirmed that CX3CL1 in RTEC does promote adhesion of cells bearing the cognate receptor. Given that CX3CL1 and thromboxane A2 are both found in similar inflammatory conditions, are both present early in the inflammatory process and that stimulation of the TP receptor has been shown to regulate other chemokines, we next evaluated the effect of stimulation of TP on CX3CL1. We found that both total and surface cellular levels of CX3CL1 were reduced following stimulation of TP. A maximal nadir was present after 30-60 minutes and the levels returned to baseline by 4 hours. The mechanism for the loss of CX3CL1 was then assessed. CX3CL1 is known to recycle between the cell surface and an internal compartment. No effect of TP stimulation was seen on the endocytosis or exocytosis of CX3CL1. Stimulation of TP was however, shown to stimulate tumour necrosis factor-a converting enzyme (TACE) via ERK phosphorylation. TACE inducibly cleaves CX3CLI, releasing the soluble chemokine. TACE siRNA was used to knock down TACE gene expression and this prevented the loss of cellular CX3CL1, confirming that TP stimulation induces TACE cleavage of CX3CL1. T he results of further experiments are discussed in the discussion chapter.
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42

Alammari, Dalia Muhammed. "Comparative in vitro analyses of the effect of immunoglobulin λ light chain and fatty acid free albumin on proximal tubular epithelial cells-involvement of megalin phosphorylation." Thesis, University of Leicester, 2016. http://hdl.handle.net/2381/38821.

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Kidney disease is a major challenge for health care systems, and the prevalence is increasing. Proteinuria is a hallmark of progressive renal dysfunction and describes the pathological excess of plasma proteins in urine, mainly albumin. Multiple Myeloma is a cancer of plasma cells that leads to excessive presence of free light chain protein (FLC) in blood. Renal failure due to overproduction of FLC and the associated light chain proteinuria occurs as a result of decreased renal function or as a direct toxic effect on the proximal tubular cells (PTCs) by excessive protein. Proteins are normally reabsorbed by endocytosis via megalin receptor that binds proteins and mediates their uptake. Exceeding the proximal tubular epithelial cells (PTECs) reabsorption capacity might trigger inflammation detrimental to the kidney. In proteinuric nephropathy the cytoplasmic tail of megalin (MegCT) is phosphorylated after interaction between proteins and megalin on the PTECs, which activates signalling cascades that regulate the phosphorylation. An in vitro proteinuric model was established using HK2 cells (a proximal tubular epithelial cell line derived from normal human kidney) treated with high concentrations of essentially fatty acid free human serum albumin (FAF-HSA) or lambda light chain (λ-LC) isolated and purified from the urine of a myeloma patient, to induce cellular damage. The potential pathogenic role for FAF-HSA and λ-LC on HK2 cells was examined. Also, renal toxicity that comes from the intracellular signalling through phosphorylation of MegCT was addressed by utilising antibodies directed against specific phosphorylation site (PPPSP) of the intracellular portion of megalin in HK2 cells stimulated with different concentrations of FAF-HSA and λ-LC, so-called pre-stimulated HK2. In vitro analyses showed (i) a detrimental effect of FAF-HSA and λ-LC on viability of HK2, (ii) phosphorylation of the cytoplasmic tail of megalin in pre-stimulated HK2 cells. (iii) Production of inflammatory cytokines and H2O2 generation, activation of autophagy process and increase in several kidney biomarkers/ injury mediators, which are involved in different pathways in response to protein overload. All these reasons are likely to contribute to direct PTECs injury and kidney failure in patients. Potentially these mechanisms may be attractive for drug development to benefit patients with kidney failure and help to inhibit the progression of proteinuric nephropathy and as such may save lives.
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43

Sheremet, Andriy. "Bioinspired polyethersulfone-based hollow fiber membranes as the scaffolds in renal assist device for protein-bound toxins removal from blood." Master's thesis, Faculdade de Ciências e Tecnologia, 2014. http://hdl.handle.net/10362/13308.

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Dissertation for obtaining the Master degree in Membrane Engineering
Erasmus Mundus Master in Membrane Engineering
Using bioartificial kidney is the promising approach for removal of non-dializable, proteinbound uremic toxins, which are responsible for high mortality and morbidity in treating kidney failure related conditions. Additionaly, bioartificial kidney device could perform the physiological roles of the kidney such as metabolic replacement, endocrine function and immunomodulation. In the current work two commercial polyethersulfone-based membranes, Gambro HCO 1100 and Membrana MicroPES TF10 used in haemofiltration and plasma separation applications respectively were investigated. To provide adequate cytocompatibility of the membrane biomimetic, biomimetic double layer coating was developed. First, the membranes were coated with musselinspired synthetic polydopamine film, following with the coating of Collagen Type IV. Transport properties of the coated and native membranes were investigated. Increase in pure water permeability of the coated HCO 1100 membranes was observed. Membrane surface hydrophilization was assumed as the major factor responsible for the effect. Membrane permeabilities for bovine serum albumin and immunoglobulin G solutions were studied. Significant increase in protein rejection was observed for double coated HCO 1100 membranes with small or no effect of the double coated MicroPES TF10 membranes. Next, formation of confluent monolayers of the renal epithelial cells on the membrane scaffolds was studied. Cell seeding strategy was developed and two seeding conditions were tested. Specifically, the cells were allowed to adhere to the biomimetic membranes passively, and the negative pressure was applied to facilitate cell adhesion. After cultivation in semi-batch conditions the monolayer formation was examined. Confluent monolayers were observed for the conditions with passive cell adherence for the both membranes. Cell contacts formation and cell polarization were confirmed with the staining for ZO-1 protein. Applying the pressure to facilitate cell adhesion, on the contrary, resulted in the loss of cell ability to form functional monolayers.
EM3E Master is an Education Programme supported by the European Commission, the European Membrane Society (EMS), the European Membrane House (EMH), and a large international network of industrial companies, research centres and universities
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44

Komuraiah, Myakala. "Proliferation Signal Inhibitor associated proteinuria in a renal transplant recipient: Dysfunction of proximal tubular epithelial cells is a result of decreased cubilinand/or megalin expression? : Proliferation Signal Inhibitor associated Proteinuria." Thesis, University of Skövde, School of Life Sciences, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-3885.

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Background The proliferation signal inhibitors (PSIs) sirolimus (SRL) and everolimus (ERL) are the potent immunosuppressive drugs using in organ transplantation and has been used successfully in renal transplant recipients (RTX) as well. PSIs are the key factors to overcome the allograft rejections after successful organ transplantation since the immune system starts to react against the graft. SRL and ERL prevents the action of immune system b inhibits the proliferation of T- and B-cells by inhibiting the intracellular signaling of interleukin-2. The presence of excess amount of serum proteins including albumin in the urine is considered as proteinuria, which reflects the loss of kidney function. The occurrence of proteinuria can be the result of abnormal glomerular filtration and/or impaired tubular endocytic function of renal proximal tubular epithelial cells (PTECs). Megalin and cubulin are two scavenger receptors present on epical surface of PTECs and involved in reabsorption of proteins after glomerular ultrafiltration process in the kidney. Proteinuria appears too high in renal transplanted patients during ongoing   treatment with PSIs.

Aim Our study aimed to investigate and correlate the expression level of megalin and cubilin and albumin uptake in PTEC of renal transplanted patients before and after conversion to PSI.

Methods To retrieve the maximal expression of our interest molecules in renal PTECs, we optimized antigen retrieval (AR) method and primary antibody dilution for each molecule separately. An optimization experiment was performed on 3 different normal patients renal biopsies were used. Later, human renal biopsy specimens originated from 4 different renal transplanted patients were used in this study. From all the 4 patients biopsy specimens were taken before and ongoing administration of PSIs (SRL, ERL). The expression of megalin, cubilin and albumin uptake in PTEC of renal transplant patients was determined by immunohistochemical staining.

Results Based on the optimization experiments, we selected the AR method and primary antibody dilution for the expression of megalin, cubilin and albumin uptake. In 4 renal transplanted patients following administration of PSIs results in patients 1, 2, 3 expression of megalin, cubilin and albumin uptake during ongoing PSI treatment was not comparable or even more intense than before PSIs introduction. The expression of megalin, cubilin and albumin uptake was reduced in patient 4 during ongoing PSI treatment.

Conclusion Our findings suggest that the renal transplant patient 4 developed proteinuria during PSI medication. The expression of megalin, cubilin and albumin uptake was markedly decreased during ongoing PSI treatment in patient 4. We concluded that there is a direct link between PSI medication and tubular dysfunction, which might cause proteinuria

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45

Silva, Crysthiane Saveriano Rubião. "Apoptose precoce, proliferação celular sincrônica tardia e perfil de expressão de proteínas ao complexo esclerose tuberosa e às doenças renais policísticas durante tubulogênese in vitro." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/5/5160/tde-01082013-145925/.

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O complexo esclerose tuberosa (CET) e as doenças renais policísticas autossômica dominante (DRPAD) e autossômica recessiva (DRPAR) são doenças monogênicas associadas a cistogênese renal. Os produtos dos genes mutados nessas enfermidades, respectivamente tuberina e hamartina para CET, policistina-1 (PC1) e policistina-2 para DRPAD, e poliductina/fibrocistina para DRPAR, modulam proliferação, diferenciação, apoptose, crescimento e/ou migração celular. Neste estudo empregamos um sistema tridimensional de cultura de células IMCD para caracterizar os perfis de expressão dessas proteínas durante a tubulogênese. Usando uma matriz de colágeno tipo I/Matrigel e fator de crescimento de hepatócito (HGF), a formação de estruturas alongadas se iniciou dois dias após o plaqueamento in vitro (2 DIV), ao passo que o desenvolvimento de lúmen ocorreu entre 10-14 DIV. A marcação para caspase-3 ativa foi mais intensa nas fases iniciais da tubulogênese, enquanto a marcação para Ki-67 foi uniformemente pronunciada em estágios mais tardios. A tuberina e a hamartina apresentaram expressão citoplasmática e co-localização acentuada em 6 e 12 DIV. A PC1 apresentou maior expressão nas porções ramificadas dos túbulos que nas não ramificadas no 12 DIV, um padrão não verificado para a PC2. Estas proteínas exibiram expressão citoplasmática, assim como expressão ocasional e pontual na membrana plasmática. PD1 também apresentou expressão citoplasmática. Nossos dados sugerem que a apoptose e a ciclagem celular sincrônica durante a tubulogênese in vitro são mais acentuadas, respectivamente, em fases mais precoces e mais tardias da formação tubular. Nossos achados demonstram, além disso, que as proteínas relacionadas ao CET e às DRPs são expressas in vitro durante a tubulogênese, apoiando um papel importante para a interação tuberina-hamartina na formação tubular, e são consistentes com o padrão de expressão diferencial da PC1 observado durante a nefrogênese
Tuberous sclerosis complex (TSC) and autosomal dominant and recessive polycystic kidney diseases (ADPKD and ARPKD) are monogenic diseases associated with renal cystogenesis. The products of the genes mutated in these disorders, respectively tuberin and hamartin for TSC, and polycystin-1 (PC1), polycystin-2 (PC2) and polyductin/fibrocystin (PD1) for PKD, modulate cell proliferation, differentiation, apoptosis, growth and/or migration. We have employed an IMCD tridimensional cell culture system to characterize their expression profiles along tubulogenesis. Using a type I collagen/Matrigel matrix and hepatocyte growth factor (HGF), the formation of elongated structures initiated 2 days after in vitro plating (2 DIV) while lumen developed between 10-14 DIV. Active caspase-3 labeling was more intense in initial phases of tubulogenesis while Ki-67 staining was uniformly pronounced in later stages. Tuberin and hamartin showed cytoplasmic expression and marked co- localization at 6 and 12 DIV. PC1 displayed higher expression in branching than non- branching portions of the tubules at 12 DIV, a pattern not verified for PC2. These proteins presented cytoplasmic and occasional, punctate membrane expression. PD1 also showed cytoplasmic expression. Our data suggest that apoptosis and synchronous cell cycling during in vitro tubulogenesis are more remarkable, respectively, in early and later steps of tubule formation. In addition, our findings demonstrate that the TSC and PKD proteins are expressed in vitro during tubulogenesis, supporting an important role for tuberin-hamartin interaction in tubular formation, and are consistent with the differential PC1 expression pattern observed during nephrogenesis
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46

Toutain, Hervé. "Développement et caractérisation de modèles expérimentaux pour l'étude ex-vivo et in-vitro de la cellule tubulaire proximale de rein de lapin." Rouen, 1989. http://www.theses.fr/1989ROUES036.

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Une suspension de cellules tubulaires proximales de rein de lapin est isolée par une nouvelle méthode qui ne fait pas intervenir d'enzymes protéolytiques. Ces cellules, après une caractérisation biochimique, morphologique, et métabolique, sont séparées en deux populations hautement purifiées par une technique d'électrophorèse ou flux libre en veine liquide. Présentation d'un modèle de culture primaire de cellules tubulaires proximales de rein de lapin
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47

Naillat, F. (Florence). "Roles of Wnt4/5a in germ cell differentiation and gonad development & ErbB4 in polarity of kidney epithelium." Doctoral thesis, Oulun yliopisto, 2011. http://urn.fi/urn:isbn:9789514295751.

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Abstract The embryonic urogenital system generates the metanephric kidneys, the gonads and the adrenal glands, and its development is based on sequential and reciprocal cell and tissue interactions. The mechanisms which regulate urogenital ontogeny are still poorly understood. In this thesis, the roles of Wnt-4 and ErbB4 functions in gonad and kidney development were analysed by using in vivo functional genomic technologies. Wnt-4 is crucial in female development since its absence leads to a partial female to male sex reversal. We found that Wnt-4 mediated the interactions between the somatic and the germ cells and played a role in meiosis which is regulated in part by the secreted signal retinoic acid (RA). Expression of certain meiosis-controlling genes (Stra8, Spo11) was inhibited in the Wnt-4 deficient germ cells, while certain pluripotency genes (Oct4, Fgf9, Sox2 and Dnmt3l) were activated similarly as in the wild-type male gonad. In addition to this, we noted that a gene encoding for a Cyp26b1 enzyme, which degrades RA in the embryonic testis, was ectopically expressed in the Wnt-4 deficient ovary. Microarray analysis was used to identify candidate Wnt-4 target genes by using the Wnt-4 knock-out mouse. Of these genes, Runx-1 may represent a novel signalling target to mediate Wnt-4 activity in the control female development The role of receptor-tyrosine kinase ErbB4 in kidney development was studied by using both in vivo gain and loss of function approaches. In the gain-of-function situation, we found that certain markers for the epithelial tubules and collecting ducts lost their polarized expression pattern. At the same time, the orientation of the cells in the kidney tubules was deregulated and an increase in cell proliferation was noticed. We suggest that the observed defects gave rise to an increase in the tubule diameter and to cyst formation in the kidney cortex. In the loss-of-function mouse, the lack of ErbB4 expression led to a similar phenotype as with the gain of function, and the renal functions of the mutant adult kidneys were compromised. In conclusion, the results point to specific roles for Wnt-4 and ErbB4 in the control of urogenital development. Wnt-4 appears to be crucial in sustaining proper female somatic cell and germ cell differentiation, and maintenance of gonad development during and after the sex determination event, while ErbB4 activity is critical for the regulation of tubular growth in embryonic kidney development
Tiivistelmä Sekä nisäkkään jälkimunuainen, lisämunuainen että sukurauhanen kehittyvät alkion urogenitaalialueen järjestelmästä ja solu- ja kudosvuorovaikutukset ohjaavat elinkehitysprosessia. Tapahtuman molekyylitason mekanismit ovat kuitenkin huonosti tunnettuja. Tässä väitöskirjatyössä tutkittiin Wnt-4 signaalin tehtäviä sukurauhasen ja ErbB4- proteiinin munuaisen kehityksessä. Wnt-4 signaali on keskeinen naisen sukupuolisuuden kehityksessä, koska signaalin puutos aiheuttaa alkion sukupuolen osittaisen kääntymisen naaraasta koiraaksi. Tarkastelimme aluksi sitä, välittääkö Wnt-4 itusolujen ja sukurauhasen somaattisten solujen vuorovaikutuksia ohjaten itusolujen meioosia, jota mm. A-vitamiini säätelee. Havaitsimme, että Wnt-4 geeni puuttuessa tietyt meioosia säätelevät geenit kuten Stra8 ja Spo11 olivat heikentyneet, kun taas solujen monikykyisyyteen liittyvät geenit kuten Oct4, Fgf9, Sox2 ja Dnmt3l aktivoituivat vastaavalla tavalla kuin havaitaan normaalisti koirasalkion kivesaiheessa. Tämän lisäksi havaitsimme, että Cyp26b1-geeni, joka johtaa A-vitamiinin hajoamiseen alkiossa ja estää normaalisti meioosin koirasalkion kivesaiheessa oli aktivoitunut munuaisrauhasaiheessa, jolta puuttuu Wnt-4 aktiivisuus. Tuloksemme osoittavat, että Wnt-4 säätelee osaltaan naarasalkion itusolujen meioosia. Tarkastelimme myös mikrosirututkimusten avulla niitä geenejä, joita Wnt-4 säätelee sukuelinaiheessa. Identifioimme useissa Wnt ja β-catenin signaalireittiin liittyvissä geeneissa muutoksia. Muuntuneet geenit voivat olla Wnt-4 signaalireitin kohdegeenejä. Näistä Runx-1 saattaa olla keskeinen Wnt signaalitien kohdegeeni, joka säätelee merkittävällä tavalla naaraan munarauhasen kehitystä. Väitöskirjan toisessa osassa tarkastelimme ErbB4-reseptorityrosiinikinaasin tehtäviä munuaisen kehityksen säätelyssä. ErbB4-geenin tehtäviä tutkittiin käyttäen hyväksi siirtogeenisiä malliorganismeja, joissa ErbB4-geenin määrä oli joko koholla tai ajastetusti inaktivoitu. ErbB4- geenin kokeellinen yliaktiivisuus muutti spesifisti tekijöitä, jotka säätelevät osaltaan jälkimunuaisen epiteeliputkien solujen orientaatiota ja solun jakautumista. Solujen orientaatiomuutoksen yhteydessä myös solujen jakautuminen häiriintyi. Oletuksemme on, että nämä epiteelikudoksessa tapahtuneet muutokset ovat syy, miksi kohotettu ErbB4-aktiviteetti muuttaa epiteeliputkien paksuutta ja pituutta erityisesti munuaisen pintakerroksissa. Havaitsimme myös, että ErbB4-geenin ajastettu poistaminen munuaisen epiteelikudoksessa johti hyvin samankaltaisiin, mutta vastakkaisiin muutoksiin kuin ErbB4-aktiviteetin kohottaminen. Muutokset johtivat myös muutoksiin munuaisen toiminnassa. Yhteenvetona toteamme, että näillä Wnt-4 ja ErbB4 solusignallointiin liittyvillä molekyyleillä on keskeinen tehtävä alkion munarauhasen ja munuaisen aiheen kehityksen säätelyssä. Wnt-4 ohjaa sekä itusolujen että somaattisten solujen erilaistumista ja samalla sukupuolen määräytymistä ja jatkokehitystä, kun taas ErbB4-signallointireseptorin tehtävä on avainasemassa munuaisen epiteeliputken kasvun säätelyssä
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48

Friedlander, Gérard. "Etude des facteurs qui modulent l'effet des hormones sur des cellules epitheliales d'origine renale." Paris 7, 1987. http://www.theses.fr/1987PA077204.

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49

Murugan, S. (Subramanian). "Control of nephrogenesis by Wnt4 signaling:mechanisms of gene regulation and targeting of specific lineage cells by tissue engineering tools." Doctoral thesis, Oulun yliopisto, 2012. http://urn.fi/urn:isbn:9789526200323.

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Abstract Wnt4, a member of the Wnt family of secreted factors, is essential for kidney organogenesis since the kidney fails to develop in its absence. Besides the kidney, Wnt4 signaling is involved in the control of development of several other organs such as the gonads, adrenal glands and pituitary gland. In the context of the embryonic kidney, Wnt4 signaling induces mesenchymal to epithelial transition of the progenitor cells in the metanephric mesenchyme, an early step in nephrogenesis. Wnt4 signaling may also be relevant in the development of a childhood kidney tumor, the Wilms’ tumor, that involves the function of Wilms’ tumor suppressor protein 1 (WT1). Wilms’ tumor is thought to arise from the early metanephric mesenchymal cells of the embryonic kidney, but the detailed mechanisms are not known. The main aim of this project was to study the mechanisms that regulate expression of the Wnt4 gene by using immortalized embryonic kidney mesenchyme-derived mK4 cells as a model. The Wnt4 gene expression was also analyzed in vivo in the frog embryonic pronephros. Through the use of reporter assays and a two-hybrid screen, Sox11, a member of the SoxC family of transcription factors, was identified as a synergistic protein that interacts with WT1. Immunoprecipitation studies provided further evidence that Sox11 and WT1 may physically interact with each other in the developing embryonic kidney. Indeed, Sox11 and WT1 may regulate the Wnt4 gene expression in vivo since the morpholino-based knock-down of either WT1 or Sox11 led to notable downregulation of the Wnt4 gene expression in the frog embryonic pronephros. The other general aim of this thesis was to develop novel tissue targeting and therapy tools to the cell lineages regulated by the Wnt4 signals, including the podocytes. For this purpose, we utilized mice carrying a floxed expression cassette for the avidin-LDL receptor fusion protein, Lodavin, in the constitutively active Rosa-26 locus. Three Cre driver mice, including the Wnt4-Cre knock-in line, were used to activate Lodavin expression in the respective cells of the embryonic kidney. Moreover, we generated a podocyte injury model by expressing the human receptor for diphtheria toxin specifically in the podocytes. This was achieved by crossing mice containing a floxed expression cassette for this receptor in the Rosa-26 locus with those expressing the Cre recombinase under the nephrin promoter. Administration of diphtheria toxin led initially to podocyte damage only, followed by a progression to glomerular sclerosis. As a summary, Sox11 and WT1 serve as synergistic transcription factors that may regulate expression of the Wnt4 gene in vivo. The transgenic mouse models generated and used provide the basis to generate acute and chronic kidney disease models and the potential to purify the respective cells for developing cell-based therapy avenues for the kidney. Moreover, the Lodavin-based approaches may enable targeted delivery of biotinylated small compounds, proteins, viruses or even cells and novel means for in vivo imaging and functional studies
Tiivistelmä Wnt-4 kuuluu signaloivien proteiinien Wnt-perheeseen ja sen toiminta on välttämätöntä munuaisen kehityksessä. Ilman Wnt-4 proteiinia munuainen ei kehity. Munuaisen lisäksi Wnt4-signalointi on mukana useiden muiden elinten, kuten sukurauhasten, lisämunuaisen ja aivolisäkkeen säätelyssä. Alkion munuaisessa Wnt4-signalointi saa aikaan mesenkymaalisen kantasolukon epitelisoitumisen, edustaen näin ollen nefronin kehityksen varhaisia vaiheita. Wnt4-signaloinnilla on myös merkittävä asema lapsuusiän munuaiskasvaimen, niin kutsutun Wilmsin kasvaimen kehittymisessä. Tämän tyyppisessä kasvaimessa keskeisenä on Wilmsin tuumoriproteiinin WT1:n toiminta, mutta myös Wnt4:n toiminnalla voi olla merkitystä. Wilmsin kasvaimen arvellaan saavan alkunsa varhaisista sikiöaikaisista jälkimunuaisen soluista, mutta yksityiskohtaisia mekanismeja ei vielä tunneta. Tämän projektin tarkoituksena oli tutkia Wnt4-geenin ilmentymistä sääteleviä mekanismeja käyttäen mallina mK4-soluja eli alkion munuaisesta saatuja, immortalisoituja soluja. Wnt4-geenin ilmentymistä analysoitiin myös in vivo sammakon alkion alkumunuaisessa. Tuplahybridi-analysoinnin avulla tunnistettiin transkriptiotekijäperhe SoxC:n jäsen Sox11 samantoimiseksi proteiiniksi transkriptiotekijä WT1:n kanssa Wnt4-geenin ilmentymisen säätelyssä. Immunopresipitaatiotutkimukset tukivat ajatusta, että Sox11 ja WT1 voisivat olla fyysisessä vuorovaikutuksessa säädellessään nefroninmuodostuksen alullepanossa ratkaisevan Wnt4-geenin ilmentymistä. Sox11 ja WT1 voivat mahdollisesti säädellä Wnt4-geenin ilmentymistä myös in vivo, sillä morfoliineihin perustuvissa kokeissa sekä WT1:n että Sox11:n hiljennys laski Wnt4-geenin ilmentymistasoa sammakon alkumunuaisessa. Tämän väitöstutkimuksen toinen yleinen tavoite oli kehittää uusia kudoskohdennus- ja terapiakeinoja Wnt4-signaloinnin säätelemille solulinjoille, kuten podosyyteille. Tätä tarkoitusta varten kloonattiin siirtogeeninen hiiri, jossa floksattu avidiini-LDL -reseptorifuusioproteiini, Lodavin, kohdennettiin jatkuvasti aktiiviseen Rosa-26 -lokukseen. Kolmea eri Cre-hiirilinjaa käytettiin aktivoimaan Lodavinin ilmentyminen kussakin tietyssä alkion munuaisen solupopulaatiossa. Yksi näistä Cre-linjoista oli Wnt4-Cre. Jotta kyettäisiin vahingoittamaan samoja soluja, jotka ilmentävät Lodavinia, hyödynnettiin difteriamyrkyn ihmisen reseptoria (iDTR). IDTR:n ilmentäminen tietyissä hiiren soluissa tekee ne alttiiksi tappavalle difteriamyrkylle. IDTR-perusteisen munuaisvauriomallin kehittämiseksi käytettiin floksattua iDTR-hiirimallia, ja geenin ilmentyminen aktivoitiin Wnt4-indusoiduissa munuaissolulinjoissa, erityisesti podosyyteissä Nephrin Cre -välitteisesti. NephrinCre;R26RiDTR hiiriä altistettiin difteriamyrkylle ja niiden munuaiskerästen muutoksia seurattiin. Tutkimukset antavat viitteitä siitä, että R26R-floksatut iDTR-hiiret toimivat hyvänä mallina kehitettäessä sekä akuutteja että kroonisia munuaistautimalleja. Yhteenvetona voidaan todeta, että Sox-11 ja WT-1 ovat samantoimisia transkriptiotekijöitä, jotka voivat säädellä Wnt4-geenin ilmentymistä in vivo. Tutkimuksessa kehitetyt ja käytetyt siirtogeeniset hiirimallit tarjoavat perustan kehittää sekä akuutteja että kroonisia munuaistautimalleja. Samalla ne mahdollistavat kulloistenkin solujen eristämisen uusien soluperusteisten hoitomenetelmien kehittelemiseksi. Lisäksi Lodavin-perusteiset lähestymistavat voivat mahdollistaa biotinyloitujen pienten yhdisteiden, proteiinien, virusten tai jopa solujen kuljetuksen kohdennetusti sekä avata uusia mahdollisuuksia in vivo -kuvantamiselle ja toiminnallisille tutkimuksille
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50

Henrie, Hélène. "Régulation de la dynamique des microtubules par la kinase de stress JNK dans les cellules épithéliales : caractérisation de CLIP-170 comme un nouveau substrat." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS461/document.

Full text
Abstract:
Les microtubules sont des éléments dynamiques du cytosquelette qui contrôlent à la fois l’organisation du cytoplasme, la polarité, la migration et la division cellulaire. Notre laboratoire a précédemment montré que la kinase de stress JNK (c-Jun NH2-terminal Kinase) régule la dynamique des microtubules dans les cellules épithéliales de mammifères, en augmentant les vitesses de polymérisation, ainsi que les fréquences de sauvetage (transition vers une phase de repolymérisation). Alors que certaines protéines neuronales capables de réguler la dynamique des microtubules ont été identifiées comme des substrats de JNK, leurs équivalents dans les cellules épithéliales sont largement méconnus. Dans le but de comprendre comment JNK module la dynamique des microtubules dans les cellules épithéliales de mammifère, nous avons étudié deux substrats potentiels de JNK : la -tubuline et le facteur de sauvetage CLIP-170. Nous avons bien mis en évidence in vitro, une phosphorylation de la -tubuline par JNK sur une thréonine non-consensus, mais cette phosphorylation n’a pas été retrouvée dans les cellules HeLa, suggérant que la -tubuline n’est pas un substrat naturel de JNK in vivo. Nous avons mis en évidence par ailleurs que CLIP-170 est un nouveau substrat de JNK. Dans les cellules épithéliales, JNK activée phosphoryle trois résidus (Thr25, Thr45 et Ser147) situés dans la partie N-terminale de CLIP-170 de part et d’autre du premier domaine CAP-Gly qui est nécessaire pour l’interaction avec les microtubules. Ces acides aminés présentent des différences aussi bien dans leur phosphorylation basale que dans leurs cinétiques de phosphorylation par JNK sous divers stress. De plus, nous avons trouvé que dans différentes cellules épithéliales, la phosphorylation de ces sites est conservée. In vitro, ces résidus sont directement phosphorylés par JNK, préférentiellement quand le domaine N-terminal de CLIP-170 lie la tubuline. De plus, l’expression de mutants de CLIP-170 phospho-mimétiques et non-phosphorylables a montré que la phosphorylation de chaque site augmente la fréquence des sauvetages microtubulaires. Cette modulation n’est pas corrélée à une augmentation de la capacité de CLIP-170 à former des comètes aux extrémités plus en croissance ou à être retenue aux croissements microtubulaires, qui sont des sites de sauvetage potentiels.Ce travail a permis de décrire les premières phosphorylations de CLIP-170 qui stimulent sa fonction de sauvetage in vivo. Il souligne par ailleurs la complexité des mécanismes de sauvetage, qui demeurent un aspect encore énigmatique de l’instabilité dynamique des microtubules. L’activité de JNK sur CLIP-170 ne permet d’expliquer qu’une partie des effets de la kinase sur la dynamique des microtubules, aussi la recherche d’autres protéines cibles de JNK pouvant réguler notamment leur vitesse de polymérisation, reste à entreprendre
Microtubules are dynamic cytoskeleton elements, which control cytoplasm organization, cell polarity, migration and division. Our laboratory has previously shown that the stress kinase JNK (c-Jun NH2-terminal Kinase) regulates microtubule dynamics in mammalian epithelial cells, by increasing their growth rates, and their rescue frequencies (transition towards phases of repolymerization). While several neuronal proteins regulating microtubule dynamics have been identified as JNK substrates, their counterparts in epithelial cells are largely unknown. With the aim to understand how JNK modulates microtubule dynamics in mammalian epithelial cells, we studied two putative substrates of JNK: -tubulin and the rescue factor CLIP-170. Regarding -tubulin, using an in vitro kinase assay, we found that a non-consensus threonine is actually phosphorylated by JNK, but we were not able to find this phosphorylation in HeLa cells, suggesting that -tubulin is not a natural JNK substrate. In parallel, we found that CLIP-170 is a new substrate of JNK in epithelial cells. Activated JNK phosphorylates three residues (Thr25, Thr45 and Ser147) located in the N-terminal part of CLIP-170, on each side of the first CAP-Gly domain, which is required for CLIP-170 interaction with microtubules. These residues exhibit differences in their level of basal phosphorylation and their kinetics of phosphorylation by JNK under various stresses. Moreover, we found that in different epithelial cells, the phosphorylation of these sites is conserved. Using an in vitro kinase assay, we found that all these residues are directly phosphorylated by JNK, preferentially when the N-terminal domain of CLIP-170 binds tubulin. Furthermore, using phospho-mimetic and non-phosphorylatable CLIP-170 mutants in epithelial cells, we revealed that the phosphorylation of each site increases microtubule rescues. Such modulation operates without increasing CLIP-170 capability to form comets at the microtubule growing plus ends or to accumulate at microtubule crossings, which are potential rescue sites.This work described the first phosphorylations that enhance CLIP-170 rescue factor function in vivo. It also points out to which extent rescue mechanisms are complex and remain an elusive aspect of dynamic instability. JNK-mediated phosphorylation of CLIP-170 only partly explains the kinase effects on microtubule dynamics. Therefore, identifying other JNK targets that may regulate microtubule polymerization rate, remains to be addressed
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