Journal articles on the topic 'Tubular-interstitial fibrosis'
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Wyczanska, Maja, Jana Rohling, Ursula Keller, Marcus R. Benz, Carsten Kirschning, and Bärbel Lange-Sperandio. "TLR2 mediates renal apoptosis in neonatal mice subjected experimentally to obstructive nephropathy." PLOS ONE 18, no. 11 (November 28, 2023): e0294142. http://dx.doi.org/10.1371/journal.pone.0294142.
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Urinary tract obstruction during renal development leads to inflammation, tubular apoptosis, and interstitial fibrosis. Toll like receptors (TLRs) expressed on leukocytes, myofibroblasts and renal cells play a central role in acute inflammation. TLR2 is activated by endogenous danger signals in the kidney; its contribution to renal injury in early life is still a controversial topic. We analyzed TLR2 for a potential role in the neonatal mouse model of congenital obstructive nephropathy. Inborn obstructive nephropathies are a leading cause of end-stage kidney disease in children. Thus, newborn Tlr2-/- and wild type (WT) C57BL/6 mice were subjected to complete unilateral ureteral obstruction (UUO) or sham-operation on the 2nd day of life. The neonatal kidneys were harvested and analyzed at days 7 and 14 of life. Relative expression levels of TLR2, caspase-8, Bcl-2, Bax, GSDMD, GSDME, HMGB1, TNF, galectin-3, α-SMA, MMP-2, and TGF-β proteins were quantified semi-quantitatively by immunoblot analyses. Tubular apoptosis, proliferation, macrophage- and T-cell infiltration, tubular atrophy, and interstitial fibrosis were analyzed immunohistochemically. Neonatal Tlr2-/- mice kidneys exhibited less tubular and interstitial apoptosis as compared to those of WT C57BL/6 mice after UUO. UUO induced neonatally did trigger pyroptosis in kidneys, however to similar degrees in Tlr2-/- and WT mice. Also, tubular atrophy, interstitial fibrosis, tubular proliferation, as well as macrophage and T-cell infiltration were unremarkable. We conclude that while TLR2 mediates apoptosis in the kidneys of neonatal mice subjected to UUO, leukocyte recruitment, interstitial fibrosis, and consequent neonatal obstructive nephropathy might lack a TLR2 involvement.
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Christensen, Erik I., and Pierre J. Verroust. "Interstitial fibrosis: tubular hypothesis versus glomerular hypothesis." Kidney International 74, no. 10 (November 2008): 1233–36. http://dx.doi.org/10.1038/ki.2008.421.
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Rascio, Federica, Paola Pontrelli, Giuseppe Stefano Netti, Elisabetta Manno, Barbara Infante, Simona Simone, Giuseppe Castellano, et al. "IgE-Mediated Immune Response and Antibody-Mediated Rejection." Clinical Journal of the American Society of Nephrology 15, no. 10 (September 9, 2020): 1474–83. http://dx.doi.org/10.2215/cjn.02870320.
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Background and objectivesActive antibody-mediated rejection is the main cause of kidney transplant loss, sharing with SLE the alloimmune response and the systemic activation of the IFN-α pathway. IgE-mediated immune response plays a key role in the development of SLE nephritis and is associated with IFN-α secretion. The aim of our study was to investigate IgE-mediated immune response in antibody-mediated rejection.Design, setting, participants, & measurementsThis was a cross-sectional study of 56 biopsy-proven antibody-mediated rejection study participants, 80 recipients with normal graft function/histology (control), 16 study participants with interstitial fibrosis/tubular atrophy, and six participants with SLE. We evaluated graft IgE deposition, tryptase (a mast cell marker), and CD203 (a specific marker of activated basophils) by immunofluorescence/confocal microscopy. In addition, we measured serum concentration of human myxovirus resistance protein 1, an IFN-α–induced protein, and anti-HLA IgE.ResultsWe observed a significantly higher IgE deposition in tubules and glomeruli in antibody-mediated rejection (1766±79 pixels) and SLE (1495±43 pixels) compared with interstitial fibrosis/tubular atrophy (582±122 pixels) and control (253±50 pixels). Patients with antibody-mediated rejection, but not control patients and patients with interstitial fibrosis/tubular atrophy, presented circulating anti-HLA IgE antibodies, although with a low mean fluorescence intensity. In addition, immunofluorescence revealed the presence of both mast cells and activated basophils in antibody-mediated rejection but not in control and interstitial fibrosis/tubular atrophy. The concentration of circulating basophils was significantly higher in antibody-mediated rejection compared with control and interstitial fibrosis/tubular atrophy. MxA serum levels were significantly higher in antibody-mediated rejection compared with control and correlated with the extent of IgE deposition.ConclusionsOur data suggest that IgE deposition and the subsequent recruitment of basophils and mast cells within the kidney transplant might play a role in antibody-mediated rejection.
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Eskild-Jensen, Anni, Lene Fogt Paulsen, Lise Wogensen, Ping Olesen, Lea Pedersen, Jørgen Frøkiær, and Jens Randel Nyengaard. "AT1 receptor blockade prevents interstitial and glomerular apoptosis but not fibrosis in pigs with neonatal induced partial unilateral ureteral obstruction." American Journal of Physiology-Renal Physiology 292, no. 6 (June 2007): F1771—F1781. http://dx.doi.org/10.1152/ajprenal.00479.2006.
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Obstruction-induced fibrosis is a leading cause of end-stage renal failure in children. The pathophysiological mechanisms may involve apoptosis and the renin-angiotensin system. We studied apoptosis and fibrosis in a well-established neonatal pig model with unilateral partial ureteral obstruction (PUUO) induced during ongoing nephrogenesis in 2-day-old piglets. The role of angiotensin II (ANG II) was studied using the AT1 receptor blocker CV-11974 (0.12 mg/h candesartan from age 23 to 30 days). At day 30 the kidneys were perfusion fixed and fibrosis, apoptosis, and tubular lengths were quantitated using stereological methods, picro Sirius red staining, and immunohistochemical techniques identifying activated caspase 3, aquaporin-2 (AQP2), and von Willebrand factor. The collagen content was assessed by hydroxyproline density. Neonatal induced PUUO increased interstitial and glomerular cell apoptosis and fibrosis. At this stage, PUUO did not increase tubular cell apoptosis or decrease tubular length and cell number. AT1 receptor blockade prevented the PUUO-induced interstitial and glomerular cell apoptosis but did not attenuate fibrosis. In conclusion, AT1 receptor blockade after the end of nephrogenesis may prevent interstitial and glomerular cell apoptosis but not fibrosis, suggesting that pathways not involving AT1 receptor stimulation contribute to neonatal obstruction-induced fibrosis or that prevention of interstitial cell apoptosis counteracts a potential antifibrotic effect of AT1 receptor blockade in this pig model of congenital obstructive nephropathy. Our results demonstrate that ANG II plays a role in PUUO-induced glomerular cell apoptosis.
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Wang, Shi-Nong, and Raimund Hirschberg. "Growth factor ultrafiltration in experimental diabetic nephropathy contributes to interstitial fibrosis." American Journal of Physiology-Renal Physiology 278, no. 4 (April 1, 2000): F554—F560. http://dx.doi.org/10.1152/ajprenal.2000.278.4.f554.
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Glomerular proteinuria is a risk factor for progression of chronic renal failure and contributes to renal interstitial fibrosis. In experimental diabetic glomerular sclerosis, there is translocation of high-molecular-weight growth factors, namely, hepatocyte growth factor (HGF) and transforming growth factor (TGF)-β, from plasma into tubular fluid, both of which act on tubular cells through apical membrane receptors. In the present studies, the hypothesis is examined that ultrafiltered HGF and TGF-β induce increased expression of extracellular matrix (ECM) proteins directly in tubular cells, or induce increased expression of cytokines that may act on interstitial myofibroblasts. Incubation of cultured tubular cells with recombinant human (rh) TGF-β modestly raises expression of collagen type III, but rhHGF dose dependently blocks expression of this ECM protein. Both growth factors raise fibronectin expression up to fourfold and increase expression of platelet-derived growth factor (PDGF)-BB up to sixfold, but not of fibroblast growth factor-2. Pooled, diluted glomerular ultrafiltrate that had been collected by nephron micropuncture from rats with diabetic nephropathy (24–30 wk) also raises expression of fibronectin as well as PDGF-BB in proximal tubular cells. In the presence of neutralizing antibodies that block actions of HGF and TGF-β, diabetic rat glomerular ultrafiltrate fails to increase tubular cell PDGF-BB expression. In NRK-49F renal interstitial myofibroblasts, rhPDGF-BB, in turn, raises the expression of collagen type III but not type I or fibronectin. The findings provide evidence for ultrafiltered HGF and TGF-β to contribute to interstitial accumulation of ECM proteins by direct effects on tubular cells as well as indirect mechanisms, via PDGF-BB and its action on myofibroblasts. These events may be important mechanisms of proteinuria-induced renal interstitial fibrosis and accelerated progression of chronic renal failure in diabetic nephropathy and perhaps other proteinuric glomerular diseases.
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Thomas, S. E., S. Anderson, K. L. Gordon, T. T. Oyama, S. J. Shankland, and R. J. Johnson. "Tubulointerstitial disease in aging: evidence for underlying peritubular capillary damage, a potential role for renal ischemia." Journal of the American Society of Nephrology 9, no. 2 (February 1998): 231–42. http://dx.doi.org/10.1681/asn.v92231.
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Aging is associated with a progressive decline in renal function and the development of glomerulosclerosis and interstitial fibrosis. Although many studies have addressed the cellular mechanisms of age-related glomerulosclerosis, less is known about the tubulointerstitial fibrosis. In this study, aging (24 mo) rats develop tubulointerstitial fibrosis characterized by tubular injury and focal tubular cell proliferation, myofibroblast activation, macrophage infiltration with increased immunostaining for the adhesive proteins osteopontin and intercellular adhesion molecule-1, and collagen IV deposition. Aging rats demonstrated immunostaining for endothelial nitric oxide synthase (eNOSIII) in renal tubular epithelial cells and infiltrating mononuclear cells in areas of tubulointerstitial injury, with a relative loss of staining of the peritubular capillaries compared with young rats. The aging rats also displayed focal loss of peritubular capillaries (as noted by focally decreased RECA-1 and OX-2 staining) in areas of tubulointerstitial injury. The areas of fibrosis and hypocellularity were associated with increased apoptosis of tubular and interstitial cells compared with young (3 mo) rats (25.4 +/- 5.3 versus 3.5 +/- 2.5 TUNEL-positive cells/0.25 mm2 in old versus young rats, P = 0.0001). It is concluded that tubulointerstitial fibrosis in aging is an active process associated with interstitial inflammation and fibroblast activation. The progressive loss of cells in areas of fibrosis may be due to accelerated apoptosis. Furthermore, the tubulointerstitial injury may be the consequence of ischemia secondary to peritubular capillary injury and altered eNOS expression.
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Leong, Khai Gene, Elyce Ozols, John Kanellis, David J. Nikolic-Paterson, and Frank Y. Ma. "Cyclophilin A Promotes Inflammation in Acute Kidney Injury but Not in Renal Fibrosis." International Journal of Molecular Sciences 21, no. 10 (May 22, 2020): 3667. http://dx.doi.org/10.3390/ijms21103667.
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Cyclophilin A (CypA) is a highly abundant protein in the cytoplasm of most mammalian cells. Beyond its homeostatic role in protein folding, CypA is a Damage-Associated Molecular Pattern which can promote inflammation during tissue injury. However, the role of CypA in kidney disease is largely unknown. This study investigates the contribution of CypA in two different types of kidney injury: acute tubular necrosis and progressive interstitial fibrosis. CypA (Ppia) gene deficient and wild type (WT) littermate controls underwent bilateral renal ischaemia/reperfusion injury (IRI) and were killed 24 h later or underwent left unilateral ureteric obstruction (UUO) and were killed 7 days later. In the IRI model, CypA−/− mice showed substantial protection against the loss of renal function and from tubular cell damage and death. This was attributed to a significant reduction in neutrophil and macrophage infiltration since CypA−/− tubular cells were not protected from oxidant-induced cell death in vitro. In the UUO model, CypA−/− mice were not protected from leukocyte infiltration or renal interstitial fibrosis. In conclusion, CypA promotes inflammation and acute kidney injury in renal IRI, but does not contribute to inflammation or interstitial fibrosis in a model of progressive kidney fibrosis.
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Wang, Shudan, Ming Wu, Luis Chiriboga, Chaim Putterman, Anna Broder, and H. Michael Belmont. "4336 Renal Tubular Complement C9 Deposition is Associated with Renal Tubular Damage and Fibrosis in Lupus Nephritis." Journal of Clinical and Translational Science 4, s1 (June 2020): 144. http://dx.doi.org/10.1017/cts.2020.424.
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OBJECTIVES/GOALS: Tubulointerstitial damage in lupus nephritis (LN) is a strong predictor of progression to chronic kidney disease and end stage renal disease (ESRD). While complement activation mediates glomerular injury, the role of complement in renal tubular damage has not been evaluated. We investigated the association between complement activation and tubulointerstitial fibrosis. METHODS/STUDY POPULATION: Patients with LN were selected randomly between July 2014 - July 2016. Chromogenic immunohistochemistry was performed on formalin-fixed, paraffin-embedded, 4-µm human renal biopsy sections using unconjugated, murine anti-human Complement C9 (Hycult Biotech, clone X197) as a marker of the terminal complement activation. Positive control is C3 glomerulopathy and negative control is normal kidney. Tubular basement membrane C9 staining intensity were analyzed on semiquantitative scale 0 to 3 by a renal pathologist. Interstitial fibrosis/tubular atrophy were categorized into low (0–10%), medium (11–20%), or high (≥21%). Clinical parameters were assessed at time of biopsy and 6 months post biopsy. Bivariate associations were assessed between presence of tubular C9 (C9+) and other covariates. RESULTS/ANTICIPATED RESULTS: Renal biopsies from 30 LN studied, 23 (77%) of which had proliferative LN. There were 24 (80%) women, mean (SD) age 33 (12) years. Positive tubular C9 staining was observed in 7/30 (23%) biopsies. At time of renal biopsy, C9+ patients had significantly higher urine protein, compared to C9- patients: median (IQR) 6.2g (3.3-13.1) vs. 2.4g (1.3-4.6), p<0.01. The differences persisted at 6 months after induction therapy: 1.08g (1.0-8.3) in C9+ vs. 0.68g (0.2-2.1) in C9- patients, p = 0.06. There was no significant difference in creatinine at renal biopsy between the two groups. Tubular C9 deposition was associated with interstitial fibrosis: 49% had severe interstitial fibrosis vs. none in the C9- group, p = <0.01. Higher proportion of C9+ patients had moderate NIH Chronicity index: 42.9% vs 8.7% in the C9- group, p = 0.07. DISCUSSION/SIGNIFICANCE OF IMPACT: Tubular C9 deposition is significantly associated with proteinuria, interstitial fibrosis and increased chronicity which predict progression to ESRD and high mortality. This finding suggests that complement activation in the tubules may be linked to proteinuria and contribute to mechanism in tubulointerstitial damage in LN.
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Pichler, R. H., N. Franceschini, B. A. Young, C. Hugo, T. F. Andoh, E. A. Burdmann, S. J. Shankland, C. E. Alpers, W. M. Bennett, and W. G. Couser. "Pathogenesis of cyclosporine nephropathy: roles of angiotensin II and osteopontin." Journal of the American Society of Nephrology 6, no. 4 (October 1995): 1186–96. http://dx.doi.org/10.1681/asn.v641186.
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Low-salt-diet, cyclosporine (CsA; 15 mg/kg per day)-treated rats develop striped interstitial fibrosis, arteriolar hyalinosis, and azotemia similar to the chronic nephropathy observed in humans. To examine the role of angiotensin II in this model, rats on a low-salt diet were given CsA, CsA and the angiotensin II receptor Type I antagonist Losartan (10 mg/kg per day), CsA and hydralazine/furosemide, or vehicle. At Day 35, CsA-treated rats had tubular injury, arteriolopathy of the afferent arteriole, increased expression of the monocyte-macrophage adhesive protein osteopontin, interstitial macrophage infiltration, increased interstitial transforming growth factor-beta expression, and interstitial fibrosis. This study provides new insight in both pathogenic and therapeutic aspects of CsA nephropathy. The pathogenesis of CsA nephropathy involves the expression of osteopontin by tubular epithelial cells, the level of which closely correlates with the degree of macrophage infiltration and interstitial fibrosis in all groups (r = 0.79 and 0.74, respectively; P < 0.001). Therapeutic conclusions can be drawn from the observation that both losartan and hydralazine/furosemide reduced osteopontin expression, macrophage infiltration, transforming growth factor-beta expression, and interstitial fibrosis, but did not prevent the decrease in GFR. Treatment with losartan, but not with hydralazine and furosemide, markedly reduced arteriolopathy. It was concluded that angiotensin II contributes to the vasculopathy (hyalinosis) induced by CsA. In contrast, the interstitial fibrosis mediated by CsA can be partially prevented by both an angiotensin II Type I receptor antagonist or by hydralazine and furosemide. This suggests that the interstitial fibrosis can be dissociated from the vascular effects of CsA. The beneficial effects of lowering blood pressure or vasodilation per se may be difficult to distinguish from the specific effects of angiotensin II receptor blockade.
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Wang, Hao, Yujiao Deng, Limeng He, Yan Deng, and Wei Zhang. "Renal Interstitial Fibrosis Detected on 18F-AlF-NOTA-FAPI-04 PET/CT in a Patient With Multiple Myeloma." Clinical Nuclear Medicine 48, no. 10 (September 2, 2023): 896–98. http://dx.doi.org/10.1097/rlu.0000000000004804.
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Abstract 18F-AlF-NOTA-FAPI-04 PET/CT was performed on a 58-year-old woman newly diagnosed with multiple myeloma and acute renal insufficiency. 18F-AlF-NOTA-FAPI-04 PET/CT showed increased FAPI uptake in multiple osteolytic lesions and both kidneys. Subsequent renal aspiration biopsy confirmed renal interstitial fibrosis due to subacute tubular interstitial injury. This case suggests that 18F-AlF-NOTA-FAPI-04 PET/CT may be valuable in the evaluation of renal interstitial fibrosis in patients with multiple myeloma.
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Shappell, S. B., T. Gurpinar, J. Lechago, W. N. Suki, and L. D. Truong. "Chronic obstructive uropathy in severe combined immunodeficient (SCID) mice: lymphocyte infiltration is not required for progressive tubulointerstitial injury." Journal of the American Society of Nephrology 9, no. 6 (June 1998): 1008–17. http://dx.doi.org/10.1681/asn.v961008.
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Progressive renal injury in humans and experimental animal models is characterized by tubular atrophy, infiltration of mononuclear inflammatory cells, and interstitial fibrosis. Permanent unilateral ureter ligation represents a reproducible model for investigating mechanisms of progressive kidney injury, and in the rat is characterized by tubular epithelial cell proliferation followed by apoptosis and progressive infiltration of monocytes and lymphocytes. Nevertheless, whether monocytes or lymphocytes play a dominant role in causing tubulointerstitial damage remains to be elucidated. In the current study, a model of chronic obstructive uropathy in the mouse is established and the role of lymphocyte infiltration in the evolution of the tubule and interstitial alterations is investigated. Permanent ligation of the left ureter in wild-type (C3H/HeJ) mice resulted in progressive atrophy of tubules and interstitial fibrosis compared with the contralateral kidney over a 30-d period. Immunoperoxidase studies on frozen sections taken from kidneys at 0, 3, 10, 20, and 30 d after ureter ligation showed that the tubulointerstitial injury was accompanied by a marked and progressive increase in interstitial macrophages and T lymphocytes, with no appreciable increase in B lymphocytes. No increase in inflammatory cells was detected in contralateral kidneys over the same time frame. The significance of T lymphocyte infiltration was examined by comparing the degree of tubular atrophy and interstitial fibrosis and the nature and quantity of the inflammatory infiltrate in wild-type mice and C3HSMn.C-Scid/J (SCID) mice subjected to permanent left ureter ligation. SCID mice have genetic defects in immunoglobulin and T cell receptor gene rearrangements and are devoid of circulating mature B and T lymphocytes. Wild-type and SCID mice developed tubular atrophy and interstitial volume expansion in the ligated kidney to the same degree and at the same rate. SCID mice developed a prominent and marked monocyte/macrophage infiltrate in the ligated kidney, which was essentially equal to that in wild-type mice. In contrast, consistent with the known absence of mature lymphocytes in SCID mice, there was essentially no T lymphocyte infiltration into the ligated kidney of SCID mice. These results demonstrate the effective establishment of the model of maintained unilateral ureter ligation in mice, which is readily applicable to genetic mutant strains thus allowing for specific investigation of the role of individual components of the inflammatory response in progressive tubulointerstitial injury. These studies further demonstrate that lymphocyte infiltration is not required for progressive tubular atrophy and increased interstitial fibrosis after maintained unilateral ureter ligation.
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Wen, Jin, Zhengwei Ma, Man J. Livingston, Wei Zhang, Yanggang Yuan, Chunyuan Guo, Yutao Liu, Ping Fu, and Zheng Dong. "Decreased secretion and profibrotic activity of tubular exosomes in diabetic kidney disease." American Journal of Physiology-Renal Physiology 319, no. 4 (October 1, 2020): F664—F673. http://dx.doi.org/10.1152/ajprenal.00292.2020.
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Tubular changes contribute to the development of renal pathologies in diabetic kidney disease (DKD), including interstitial fibrosis. It is unclear how tubular cells relay signals to interstitial fibroblasts. Recently, exosomes have been recognized as crucial mediators of intercellular communication. We hypothesized that exosomes secreted from tubular cells may stimulate fibroblasts for interstitial fibrosis in DKD. In this study, we isolated and purified exosomes from the renal cortex of DKD mice and high glucose-treated mouse proximal tubular cells. Compared with nondiabetic mice, exosome secretion in kidney tissues decreased in DKD mice. Likewise, high glucose incubation reduced exosome secretion in mouse kidney proximal tubular BUMPT cells. To study the effect of tubular cell exosomes on fibroblasts, exosomes from BUMPT cells were added to renal fibroblast NRK-49F cell cultures. Notably, exosomes from high glucose conditioned BUMPT cells induced higher proliferation, significant morphological change, and substantial production of fibronectin, α-smooth muscle actin, and collagen type Ι in NRK-49F fibroblasts. Proteomics analysis was further performed to profile the proteins within tubular cell exosomes. Interestingly, 22 proteins were found to be differentially expressed between tubular exosomes derived from high glucose conditioned cells and those from normal glucose conditioned cells. Cytoscape analysis suggested the existence of two protein-protein interaction networks in these exosomal differentially expressed proteins. While one of the protein-protein interaction networks comprised enolase 1 (Eno1), heat shock protein family A member 8 (Hspa8), thioredoxin 1 (Txn1), peptidylprolyl isomerase A (Ppia), phosphoglycerate kinase 1 (Pgk1), DNA topoisomerase II-β (Top2b), and β-actin (Actb), the other had the family proteins of human leucocyte antigen F (Ywhag), a component of the ND10 nuclear body (Ywhae), interferon regulatory factor-8 (Ywhaq), and human leucocyte antigen A (Ywhaz). Gene expression analysis via Nephroseq showed a correlation of Eno1 expression with DKD clinical manifestation. In conclusion, DKD is associated with a decrease in exosome secretion in renal tubular cells. Exosomes from high glucose conditioned tubular cells may regulate the proliferation and activation of fibroblasts, contributing to the paracrine signaling mechanism responsible for the pathological onset of renal interstitial fibrosis in DKD.
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Eddy, A. A. "Experimental insights into the tubulointerstitial disease accompanying primary glomerular lesions." Journal of the American Society of Nephrology 5, no. 6 (December 1994): 1273–87. http://dx.doi.org/10.1681/asn.v561273.
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Although chronic progressive tubulointerstitial (TI) disease plays a critical role in the outcome of patients with primary glomerular lesions, the basic mechanisms that generate the TI damage remain unclear. This review focuses on recent insights into this process that originate primarily from studies of animal models of glomerular injury. The acute phase, which is often clinically silent, is characterized by tubular epithelial cell injury and interstitial inflammation. Proposed mediators of tubular injury include antibodies, lysosomal enzymes, obstruction, reactive oxygen metabolites, and complement. Damaged tubules may regenerate or undergo necrosis or apoptosis. The identification of the molecular mediators of mononuclear cell recruitment to the interstitium is of current interest because of evidence that monocytes/macrophages play a key role in progressive interstitial scarring through the release of fibrosis-promoting cytokines, particularly transforming growth factor-beta 1 (TGF-beta 1). Events linked to the initiation of interstitial inflammation include the deposition of antibodies or immune complexes along the tubular basement membranes, T cell-dependent mechanisms, glomerular factors, and factors linked to proteinuria. Several molecules likely regulate the interstitial migration of circulating monocytes, although the critical mediators are presently unknown. Candidates include chemotactic factors such as intercrines, growth factors, complement, lipid factors, osteopontin, and monocyte adhesion molecules (beta 1 integrins, beta 2 integrins, and L-selectins). The hallmark of the chronic phase of TI damage is interstitial fibrosis. Of the several candidate fibrogenic cytokines, to date, only TGF-beta 1 has been studied in any detail. TGF-beta 1 is produced by interstitial inflammatory cells and appears to trigger increased matrix production by perivascular and interstitial fibroblasts. Awaiting clarification is the role of tubular cells in vivo as a source of fibrogenic cytokines or as a site of increased matrix synthesis, activities they do perform in vitro. Preliminary studies suggest that interstitial fibrosis may also be due in part to the failure of matrix degradation by metalloproteinases and plasmin as a result of the overexpression of the enzyme inhibitors. The existence of an intrarenal matrix-degrading enzyme cascade suggests that renal fibrosis may be reversible, at least to a limited extent. In summary, during the early stage of glomerular injury, numerous cellular and molecular mediators of acute interstitial disease are activated and ultimately converge on common pathways that lead to progressive renal scarring.
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Forbes, Michael S., Barbara A. Thornhill, Jordan J. Minor, Katherine A. Gordon, Carolina I. Galarreta, and Robert L. Chevalier. "Fight-or-flight: murine unilateral ureteral obstruction causes extensive proximal tubular degeneration, collecting duct dilatation, and minimal fibrosis." American Journal of Physiology-Renal Physiology 303, no. 1 (July 1, 2012): F120—F129. http://dx.doi.org/10.1152/ajprenal.00110.2012.
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Unilateral ureteral obstruction (UUO) is the most widely used animal model of progressive renal disease. Although renal interstitial fibrosis is commonly used as an end point, recent studies reveal that obstructive injury to the glomerulotubular junction leads to the formation of atubular glomeruli. To quantitate the effects of UUO on the remainder of the nephron, renal tubular and interstitial responses were characterized in mice 7 and 14 days after UUO or sham operation under anesthesia. Fractional proximal tubular mass, cell proliferation, and cell death were measured by morphometry. Superoxide formation was identified by nitro blue tetrazolium, and oxidant injury was localized by 4-hydroxynonenol and 8-hydroxydeoxyguanosine. Fractional areas of renal vasculature, interstitial collagen, α-smooth muscle actin, and fibronectin were also measured. After 14 days of UUO, the obstructed kidney loses 19% of parenchymal mass, with a 65% reduction in proximal tubular mass. Superoxide formation is localized to proximal tubules, which undergo oxidant injury, apoptosis, necrosis, and autophagy, with widespread mitochondrial loss, resulting in tubular collapse. In contrast, mitosis and apoptosis increase in dilated collecting ducts, which remain patent through epithelial cell remodeling. Relative vascular volume fraction does not change, and interstitial matrix components do not exceed 15% of total volume fraction of the obstructed kidney. These unique proximal and distal nephron cellular responses reflect differential “fight-or-flight” responses to obstructive injury and provide earlier indexes of renal injury than do interstitial compartment responses. Therapies to prevent or retard progression of renal disease should include targeting proximal tubule injury as well as interstitial fibrosis.
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Wang, S., M. Wu, L. Chiriboga, C. Putterman, B. Goilav, A. R. Broder, and H. M. Belmont. "OP0043 RENAL TUBULAR COMPLEMENT C9 DEPOSITION IS ASSOCIATED WITH RENAL TUBULAR DAMAGE AND FIBROSIS IN LUPUS NEPHRITIS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 28.2–29. http://dx.doi.org/10.1136/annrheumdis-2020-eular.2394.
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Background:Tubulointerstitial damage in lupus nephritis (LN) is a strong predictor of progression to chronic kidney disease and end stage renal disease (ESRD). While prior studies showed complement activation mediates glomerular injury (1), the role of complement in renal tubular damage has not been evaluated.Objectives:To investigate the association between complement activation and tubulointerstitial fibrosis. Specifically, to study the role of tubular complement C9 deposition as a marker of tubular damage and fibrosis in LN.Methods:LN biopsies stored in the pathology department between July 2014 to July 2016 were evaluated. Chromogenic immunohistochemistry was performed on formalin-fixed, paraffin-embedded, 4-µm human renal biopsy sections using unconjugated, murine anti-human Complement C9 (Hycult Biotech, clone X197) as a marker of the terminal complement activation. C3 glomerulopathy was used as a positive control, and normal kidney from resected tumor served as a negative control. Tubular basement membrane C9 staining intensity were analyzed on a semi-quantitative scale from 0 to 3 by a renal pathologist. The degree of Interstitial fibrosis/tubular atrophy was categorized as low (0–10%), medium (11–20%), or high (≥21%). Clinical parameters were assessed at the time of biopsy and 6 months post biopsy.Results:Renal biopsies from 30 LN were studied, 23 (77%) of which had proliferative LN (Table). There were 24 (80%) women, mean (SD) age 33 (12) years. Positive tubular C9 staining (C9+) was observed in 7 (23%) biopsies. There was no significant difference in eGFR at renal biopsy between the two groups. At the time of renal biopsy, C9+ patients had significantly higher proteinuria, compared to C9- patients: median (IQR) 6.2g (3.3-13.1) vs. 2.4g (1.3-4.6), p<0.01. The differences persisted at 6 months after induction therapy with cyclophosphamide, cellcept or clinical trial drug: 1.08g (1.0-8.3) in C9+ vs. 0.68g (0.2-2.1) in C9- patients, p=0.06 Tubular C9 deposition was associated with interstitial fibrosis: 3 out of 7 (42.9%) had severe interstitial fibrosis vs. none in the C9- group, p=<0.01. Higher proportion of C9+ patients had moderate NIH Chronicity index: 3 out of 7 (42.9%) vs 2 out of 23 (8.7%) in the C9- group, p=0.07.Table.Comparisons of C9+ and C9- biopsiesConclusion:Tubular C9 deposition is significantly associated with proteinuria, interstitial fibrosis and increased chronicity which predict progression to ESRD and mortality. Complement activation in the tubules may be linked to proteinuria and more studies are needed to elucidate its mechanism in tubulointerstitial damage in LN.References:[1]Wang S, Wu M, Chiriboga L, Zeck B, Belmont HM. Membrane attack complex (mac) deposition in lupus nephritis is associated with hypertension and poor clinical response to treatment. Semin Arthritis Rheum. 2018;48(2):256-62.Disclosure of Interests:None declared
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Haas, Mark. "Chronic allograft nephropathy or interstitial fibrosis and tubular atrophy." Current Opinion in Nephrology and Hypertension 23, no. 3 (May 2014): 245–50. http://dx.doi.org/10.1097/01.mnh.0000444811.26884.2d.
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Muramatsu, Masaki, Yoji Hyodo, Abigail Lee, Atsushi Aikawa, Carmelo Puliatti, Magdi Yaqoob, and Michael Sheaff. "Transplant nephrectomy; pathological features of 124 consecutive cases in a single center study over 10 years." Journal of Nephropathology 8, no. 3 (June 21, 2019): 23. http://dx.doi.org/10.15171/jnp.2019.23.
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Background: Transplant nephrectomy (TN) is not commonly performed but it may be essential for several indications. Objectives: This study details an in-depth evaluation of the histological changes present in TN specimens. Patients and Methods: We identified 124 consecutive TN cases between 2004 and 2014. The indication for TN was divided into four groups: acute graft loss without significant blood flow (AGL group- 47 cases); suspected ongoing rejection or graft intolerance syndrome (Rej/GIS group44 cases); infection (INF group- 24 cases); and miscellaneous reasons (MIS group- 9 cases). We examined the histological changes, including the main renal artery (MRA), intrarenal arteries, the renal vein and the ureter. Results: In AGL group, most cases showed no tubulointerstitial inflammation, interstitial fibrosis and tubular atrophy, but 74.5% had necrosis. All cases in Rej/GIS group showed severe interstitial fibrosis and tubular atrophy, since 40.9% showed severe tubulointerstitial inflammation. Glomerulitis was observed in 52.3% and transplant glomerulopathy (TG) was detected in 75.0%. Arteritis of intrarenal arteries and the MRA were detected in 70.5% and 59.1%. In INF group, 66.7% had tubulitis and 79.2% had interstitial inflammation with lymphocytes, and severe interstitial fibrosis while, tubular atrophy were detected in 66.7%. TG was detected in 62.5%. In MIS group, the histological changes were minor. Conclusions: This study provides a detailed description of the morphological characteristics associated with various indications for TN. TN will occasionally reveal unexpected and significant findings that may require specific forms of treatment to manage the patient appropriately.
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Mao, Haiping, Zhilian Li, Yi Zhou, Zhijian Li, Shougang Zhuang, Xin An, Baiyu Zhang, et al. "HSP72 attenuates renal tubular cell apoptosis and interstitial fibrosis in obstructive nephropathy." American Journal of Physiology-Renal Physiology 295, no. 1 (July 2008): F202—F214. http://dx.doi.org/10.1152/ajprenal.00468.2007.
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Although heat shock protein 72 kDa (HSP72) protects tubular epithelium from a variety of acute insults, its role in chronic renal injury and fibrosis is poorly characterized. In this study, we tested the hypothesis that HSP72 reduces apoptosis and epithelial-to-mesenchymal transition (EMT), important contributors to tubular cell injury in vitro and in vivo. In rats, orally administered geranylgeranylacetone (GGA), an agent that selectively induces HSP72, markedly reduced both apoptosis and cell proliferation in tubular epithelium and decreased both interstitial fibroblast accumulation and collagen I deposition after unilateral ureteric obstruction, a model of chronic renal tubulointerstitial fibrosis and dysfunction. In cultured renal NRK52E cells, exposure to TGF-β1 induced EMT and apoptosis, major causes of renal fibrosis and tubular atrophy, respectively. Exposure to a pan-caspase inhibitor (ZVAD-FMK) prevented TGF-β1-induced apoptosis but did not reduce EMT. In contrast, selective HSP72 expression in vitro inhibited EMT caused by TGF-β1 as indicated by preserving the E-cadherin expression level and α-smooth muscle actin induction. Small interfering RNA directed against HSP72 blocked the cytoprotective effects of HSP72 overexpression on EMT in TGF-β1-exposed cells. Taken together, our data indicate that HSP72 ameliorates renal tubulointerstitial fibrosis in obstructive nephropathy by inhibiting both renal tubular epithelial cell apoptosis and EMT.
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Wei, Qingqing, Jennifer Su, Guie Dong, Ming Zhang, Yuqing Huo, and Zheng Dong. "Glycolysis inhibitors suppress renal interstitial fibrosis via divergent effects on fibroblasts and tubular cells." American Journal of Physiology-Renal Physiology 316, no. 6 (June 1, 2019): F1162—F1172. http://dx.doi.org/10.1152/ajprenal.00422.2018.
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Renal interstitial fibrosis is a common pathological feature of chronic kidney disease that may involve changes of metabolism in kidney cells. In the present study, we first showed that blockade of glycolysis with either dichloroacetate (DCA) or shikonin to target different glycolytic enzymes reduced renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO). Both inhibitors evidently suppressed the induction of fibronectin and collagen type I in obstructed kidneys, with DCA also showing inhibitory effects on collagen type IV and α-smooth muscle actin (α-SMA). Histological examination also confirmed less collagen deposition in DCA-treated kidneys. Both DCA and shikonin significantly inhibited renal tubular apoptosis but not interstitial apoptosis in UUO. Macrophage infiltration after UUO injury was also suppressed. Shikonin, but not DCA, caused obvious animal weight loss during UUO. To determine whether shikonin and DCA worked on tubular cells and/or fibroblasts, we tested their effects on cultured renal proximal tubular BUMPT cells and renal NRK-49F fibroblasts during hypoxia or transforming growth factor-β1 treatment. Although both inhibitors reduced fibronectin and α-SMA production in NRK-49F cells during hypoxia or transforming growth factor-β1 treatment, they did not suppress fibronectin and α-SMA expression in BUMPT cells. Altogether, these results demonstrate the inhibitory effect of glycolysis inhibitors on renal interstitial fibrosis. In this regard, DCA is more potent for fibrosis inhibition and less toxic to animals than shikonin.
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Gupta, Kanishk. "Karyomegalic Interstitial Nephritis-A Rare Cause Of Chronic Tubulointerstitial Nephritis." Nephrology & Renal Therapy 6, no. 3 (December 31, 2020): 1–3. http://dx.doi.org/10.24966/nrt-7313/100042.
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Karyomegalic Interstitial Nephritis (KIN) is a rare disease, which usually presents with slowly progressive chronic kidney disease, eventually leading to end stage renal disease in early adulthood. Histological findings consist of enlarged and hyperchromatic nuclei in scattered tubular epithelial cells throughout the nephron accompanied by interstitial fibrosis around atrophic tubules.
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Warner, Gina M., Jingfei Cheng, Bruce E. Knudsen, Catherine E. Gray, Ansgar Deibel, Justin E. Juskewitch, Lilach O. Lerman, Stephen C. Textor, Karl A. Nath, and Joseph P. Grande. "Genetic deficiency of Smad3 protects the kidneys from atrophy and interstitial fibrosis in 2K1C hypertension." American Journal of Physiology-Renal Physiology 302, no. 11 (June 1, 2012): F1455—F1464. http://dx.doi.org/10.1152/ajprenal.00645.2011.
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Although the two-kidney, one-clip (2K1C) model is widely used as a model of human renovascular hypertension, mechanisms leading to the development of fibrosis and atrophy in the cuffed kidney and compensatory hyperplasia in the contralateral kidney have not been defined. Based on the well-established role of the transforming growth factor (TGF)-β signaling pathway in renal fibrosis, we tested the hypothesis that abrogation of TGF-β/Smad3 signaling would prevent fibrosis in the cuffed kidney. Renal artery stenosis (RAS) was established in mice with a targeted disruption of exon 2 of the Smad3 gene (Smad3 KO) and wild-type (WT) controls by placement of a polytetrafluoroethylene cuff on the right renal artery. Serial pulse-wave Doppler ultrasound assessments verified that blood flow through the cuffed renal artery was decreased to a similar extent in Smad3 KO and WT mice. Two weeks after surgery, systolic blood pressure and plasma renin activity were significantly elevated in both the Smad3 KO and WT mice. The cuffed kidney of WT mice developed renal atrophy (50% reduction in weight after 6 wk, P < 0.0001), which was associated with the development of interstitial fibrosis, tubular atrophy, and interstitial inflammation. Remarkably, despite a similar reduction of renal blood flow, the cuffed kidney of the Smad3 KO mice showed minimal atrophy (9% reduction in weight, P = not significant), with no significant histopathological alterations (interstitial fibrosis, tubular atrophy, and interstitial inflammation). We conclude that abrogation of TGF-β/Smad3 signaling confers protection against the development of fibrosis and atrophy in RAS.
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Wu, Jinhao, Chao Huang, Gang Kan, Hanyu Xiao, Xiaoping Zhang, and Jun Yang. "Silymarin Regulates Tgf-β1/Smad3 Signaling Pathway and Improves Renal Tubular Interstitial Fibrosis Caused by Obstructive Nephropathy." Current Topics in Nutraceutical Research 19, no. 4 (March 17, 2021): 508–13. http://dx.doi.org/10.37290/ctnr2641-452x.19:508-513.
Full textAbstract:
Obstructive nephropathy often leads to renal tubulointerstitial fibrosis. Understanding of the pathogenesis of renal tubulointerstitial fibrosis caused by obstructive nephropathy is crucial to the development of effective therapeutic drugs to improve the prognosis of the patients. Silymarin, a polyphenolic flavonoid extracted from plants, has been shown to exhibit antiinflammatory and antioxidant effects ameliorating liver and kidney damage. However, the effect of silymarin on renal fibrosis in obstructive nephropathy remains to be explored. In this study, we found silymarin improved interstitial fibrosis and apoptosis induced by TGF-β1 and ameliorated oxidative damage. Our data further confirmed that silymarin regulates the TGF-β1/ Smad3 signaling pathway, and therefore improves renal tubular interstitial fibrosis caused by obstructive nephropathy.
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Kimura, Kuniko, Masayuki Iwano, Debra F. Higgins, Yukinari Yamaguchi, Kimihiko Nakatani, Koji Harada, Atsushi Kubo, et al. "Stable expression of HIF-1α in tubular epithelial cells promotes interstitial fibrosis." American Journal of Physiology-Renal Physiology 295, no. 4 (October 2008): F1023—F1029. http://dx.doi.org/10.1152/ajprenal.90209.2008.
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Chronic hypoxia accelerates renal fibrosis. The chief mediator of the hypoxic response is hypoxia-inducible factor 1 (HIF-1) and its oxygen-sensitive component HIF-1α. HIF-1 regulates a wide variety of genes, some of which are closely associated with tissue fibrosis. To determine the specific role of HIF-1 in renal fibrosis, we generated a knockout mouse in which tubular epithelial expression of von Hippel-Lindau tumor suppressor (VHL), which acts as a ubiquitin ligase to promote proteolysis of HIF-1α, was targeted. We investigated the effect of VHL deletion (i.e., stable expression of HIF-1α) histologically and used the anti-HIF-1α agent [3-(5′-hydroxymethyl-2′-furyl)-1-benzyl indazole] (YC-1) to test whether inhibition of HIF-1α could represent a novel approach to treating renal fibrosis. The area of renal fibrosis was significantly increased in a 5/6 renal ablation model of VHL−/−mice and in all VHL−/−mice at least 60 wk of age. Injection of YC-1 inhibited the progression of renal fibrosis in unilateral ureteral obstruction model mice. In conclusion, HIF-1α appears to be a critical contributor to the progression of renal fibrosis and could be a useful target for its treatment.
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VIELHAUER, VOLKER, HANS-JOACHIM ANDERS, MATTHIAS MACK, JOSEF CIHAK, FRANK STRUTZ, MANFRED STANGASSINGER, BRUNO LUCKOW, HERMANN-JOSEF GRÖNE, and DETLEF SCHLÖNDORFF. "Obstructive Nephropathy in the Mouse: Progressive Fibrosis Correlates with Tubulointerstitial Chemokine Expression and Accumulation of CC Chemokine Receptor 2- and 5-Positive Leukocytes." Journal of the American Society of Nephrology 12, no. 6 (June 2001): 1173–87. http://dx.doi.org/10.1681/asn.v1261173.
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Abstract. The infiltration of leukocytes plays a major role in mediating tubulointerstitial inflammation and fibrosis in chronic renal disease. CC chemokines participate in leukocyte migration and infiltration into inflamed renal tissue. Because CC chemokine-directed leukocyte migration is mediated by target cell expression of a group of CC chemokine receptors, this study examined the expression of CC chemokines and their receptors during initiation of tubulointerstitial fibrosis after unilateral ureteral obstruction in C57BL/6 mice. Obstructed kidneys developed hydronephrosis, tubular cell damage, interstitial inflammation, and fibrosis. From days 2 to 10, a progressive interstitial influx of F4/80+ macrophages and CD3+ lymphocytes occurred (macrophages, 4-fold; lymphocytes, 20-fold at day 10, compared with contralateral control kidneys). In parallel, the number of activated fibroblast-specific protein 1+ fibroblasts and interstitial collagen IV accumulation increased from days 2 to 10. The mRNA expression of CC chemokines (predominantly monocyte chemoattractant protein-1 [MCP-1]/CCL2, RANTES/CCL5) and their receptors CCR1, CCR2, CCR5 increased progressively from days 2 to 10. Byin situhybridization, a prominent interstitial mRNA expression of MCP-1 and RANTES and their receptors CCR2 and CCR5 localized to interstitial mononuclear cell infiltrates. MCP-1 and RANTES expression was also seen in tubular epithelial cells. Fluorescence-activated cell sorter analysis of single-cell suspensions from obstructed kidneys revealed a prominent expression of CCR2 and CCR5 by infiltrating macrophages, whereas most lymphocytes expressed CCR5 only. These data demonstrate an increased expression of MCP-1/CCL2 and RANTES/CCL5 at sites of tubulointerstitial damage and progressive fibrosis during unilateral ureteral obstruction that correlates with simultaneous accumulation of interstitial macrophages and T lymphocytes expressing the respective surface receptors CCR2 and CCR5. The chemokine receptor—mediated leukocyte influx into the tubulointerstitium could offer a new potential target for therapeutic intervention in progressive renal tubulointerstitial fibrosis.
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Kuruş, Meltem, Murat Ugras, and Mukaddes Esrefoglu. "Effect of resveratrol on tubular damage and interstitial fibrosis in kidneys of rats exposed to cigarette smoke." Toxicology and Industrial Health 25, no. 8 (September 2009): 539–44. http://dx.doi.org/10.1177/0748233709346755.
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The aim of this study was to evaluate the effect of resveratrol on kidney tissue of rats exposed to cigarette smoke. Forty adult male Wistar Albino rats were divided into four groups. Animals in group 1 was the control group. For 6 weeks, group 2 was exposed to cigarette smoke; group 3 received daily intraperitoneal injections of resveratrol (10 mg/kg/d); and group 4 was exposed to both cigarette smoke and intraperitoneal resveratrol. All rats were sacrificed with cervical dislocation. The kidney tissues were obtained, fixed in Bouin’s fixative and embeded in paraffin blocks. Samples were sectioned to 4-5 microns thickness, stained with hematoxylin/eosin (H/E), Masson’s trichromic, periodic acid-schiff (PAS) and were examined by light microscopy for tubular injury and interstitial fibrosis. Results were compared by non-parametric tests. Hydropic degeneration, tubular atrophy, tubulo-interstitial fibrosis, interstitial cell infiltration, vacuolar degeneration and desquamation were prominent in group 2. In group 4, hydropic degeneration, epithelial cell vacuolization and desquamation was not observed, but occasional tubular atrophy and dilation were observed. Our study suggests that, some morphological alterations in the rat kidney, due to cigarette smoke may be prevented by resveratrol.
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Burdmann, E. A., T. F. Andoh, C. C. Nast, A. Evan, B. A. Connors, T. M. Coffman, J. Lindsley, and W. M. Bennett. "Prevention of experimental cyclosporin-induced interstitial fibrosis by losartan and enalapril." American Journal of Physiology-Renal Physiology 269, no. 4 (October 1, 1995): F491—F499. http://dx.doi.org/10.1152/ajprenal.1995.269.4.f491.
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The pathogenesis of renal scarring in chronic cyclosporin nephropathy is unknown. In this study, we evaluated the effects of renin-angiotensin system blockade by enalapril and losartan in a salt-dependent model of cyclosporin-associated chronic tubulointerstitial fibrosis (TIF). Rats kept on normal or low-salt diet were given cyclosporin, cyclosporin+enalapril, cyclosporin+losartan, cyclosporin+enalapril#losartan, or vehicle for 14 and 28 days. Cyclosporin reduced glomerular filtration rate (GFR) in rats fed either diet, but only salt-depleted animals developed significant TIF. Cyclosporin also impaired renal concentrating ability and caused tubular enzymuria. Renin-angiotensin system blockade decreased blood pressure (BP) and promoted afferent arteriolar vasodilatation. Losartan reduced plasma renin activity and prevented cyclosporin-induced increment of cortical alpha 1(I) procollagen mRNA. Renin-angiotensin blockade did not improve GFR and tubular function; however, it strikingly prevented TIF development, even in presence of very low BP. Rats treated with cyclosporin, hydralazine, and furosemide achieved BP values similar to losartan or enalapril groups, but there was no protection against interstitial fibrosis development. These results suggest that cyclosporin-related chronic interstitial injury is mediated by angiotensin II and that the mechanisms promoting the interstitial scarring can be dissociated from glomerular and tubular dysfunction in cyclosporin nephropathy.
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Pang, Maoyin, Jagan Kothapally, Haiping Mao, Evelyn Tolbert, Murugavel Ponnusamy, Y. Eugene Chin, and Shougang Zhuang. "Inhibition of histone deacetylase activity attenuates renal fibroblast activation and interstitial fibrosis in obstructive nephropathy." American Journal of Physiology-Renal Physiology 297, no. 4 (October 2009): F996—F1005. http://dx.doi.org/10.1152/ajprenal.00282.2009.
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Activation of renal interstitial fibroblasts is critically involved in the development of tubulointerstitial fibrosis in chronic kidney diseases. In this study, we investigated the effect of trichostatin A (TSA), a specific histone deacetylase (HDAC) inhibitor, on the activation of renal interstitial fibroblasts in a rat renal interstitial fibroblast line (NRK-49F) and the development of renal fibrosis in a murine model of unilateral ureteral obstruction (UUO) . α-Smooth muscle actin (α-SMA) and fibronectin, two hallmarks of fibroblast activation, were highly expressed in cultured NRK-49F cells, and their expression was inhibited in the presence of TSA. Similarly, administration of TSA suppressed the expression of α-SMA and fibronectin and attenuated the accumulation of renal interstitial fibroblasts in the kidney after the obstructive injury. Activation of renal interstitial fibroblasts was accompanied by phosphorylation of signal transducer and activator of transcription 3 (STAT3), and TSA treatment also abolished these responses. Furthermore, inhibition of the STAT3 pathway with AG490 inhibited expression of α-SMA and fibronectin in NRK-49F cells. Finally, TSA treatment inhibited tubular cell apoptosis and caspase-3 activation in the obstructive kidney. Collectively, we suggest that pharmacological HDAC inhibition may induce antifibrotic activity by inactivation of renal interstitial fibroblasts and inhibition of renal tubular cell death. STAT3 may mediate those actions of HDACs.
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Quimby, Jessica M., Shannon M. McLeland, Rachel E. Cianciolo, Katharine F. Lunn, Jody P. Lulich, Andrea Erikson, and Lara B. Barron. "Frequency of histologic lesions in the kidneys of cats without kidney disease." Journal of Feline Medicine and Surgery 24, no. 12 (December 2022): e472-e480. http://dx.doi.org/10.1177/1098612x221123768.
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Objectives In humans, renal aging is associated with an increased frequency of glomerulosclerosis, interstitial fibrosis, inflammation and tubular atrophy. The purpose of this study was to describe the frequency of renal histopathologic lesions in cats without kidney disease. Methods A cross-sectional study of archival kidney tissue from 74 cats without kidney disease (serum creatinine <1.6 mg/dl; urine specific gravity >1.035) was carried out: 0–4 years (young, n = 18); 5–9 years (mature, n = 16); 10–14 years (senior, n = 34), 15+ years (geriatric, n = 6). Glomerulosclerosis, tubular atrophy, interstitial inflammation and fibrosis, and the presence or absence of lipid in the interstitium and tubules were scored by a pathologist masked to clinical data. Statistical analyses were performed as appropriate. Results Geriatric cats had significantly more glomerulosclerosis than mature ( P = 0.01) and young cats ( P = 0.004). Senior cats had significantly more glomerulosclerosis than young cats ( P = 0.006). Glomerulosclerosis was weakly positively correlated with age ( r = 0.48; P <0.0001). Geriatric cats had significantly more tubular atrophy than mature ( P = 0.02) and young cats ( P <0.0001). Senior cats had significantly more tubular atrophy than young cats ( P <0.0001). Geriatric cats had significantly more inflammation than senior cats ( P = 0.02), mature cats ( P = 0.01) and young cats ( P <0.0001). Senior cats had significantly more inflammation than young cats ( P = 0.004). Geriatric and senior cats had significantly more fibrosis than young cats ( P = 0.01 and P = 0.04, respectively). Frequency of tubular lipid increased with age (young: 28%; mature: 56%; senior: 79%; geriatric: 100%) as did the frequency of interstitial lipid (young: 22%, mature: 56%, senior: 85%, geriatric: 100%). Conclusions and relevance Evidence of renal aging exists in cats. These changes imply that the aging kidney may be more susceptible to injury and impaired healing.
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Debelle, Frédéric D., Joëlle L. Nortier, Eric G. De Prez, Christian H. Garbar, Anne R. Vienne, Isabelle J. Salmon, Monique M. Deschodt-Lanckman, and Jean-Louis Vanherweghem. "Aristolochic Acids Induce Chronic Renal Failure with Interstitial Fibrosis in Salt-Depleted Rats." Journal of the American Society of Nephrology 13, no. 2 (February 2002): 431–36. http://dx.doi.org/10.1681/asn.v132431.
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ABSTRACT. Chinese-herb nephropathy (CHN) is a rapidly progressive renal fibrosis associated with the intake of a Chinese herb (Aristolochia fangchi) containing nephrotoxic and carcinogenic aristolochic acids (AA). This study attempted to reproduce the main features of human CHN (renal failure, tubular atrophy, and interstitial fibrosis) in a rat model similar to that of cyclosporin-induced nephropathy. Salt-depleted male Wistar rats received daily subcutaneous injections of either 1 mg/kg body wt AA (low-dose AA group), 10 mg/kg body wt AA (high-dose AA group), or vehicle (control group) for 35 d. On days 10 and 35, assessment of renal function, measurements of urinary excretion of glucose, protein, and leucine aminopeptidase, and histologic analyses were performed (six rats euthanized/group). High-dose AA induced glucosuria, proteinuria, and elevated serum creatinine levels and reduced leucine aminopeptidase enzymuria on days 10 and 35, whereas low-dose AA had no significant effect. Tubular necrosis associated with lymphocytic infiltrates (day 10) and tubular atrophy surrounded by interstitial fibrosis (day 35) were the histologic findings for the high-dose AA-treated rats. In both AA groups, urothelial dysplasia was also observed, as well as fibrohistiocytic sarcoma at the injection site. A short-term model of AA-induced renal fibrosis was established in salt-depleted Wistar rats. These results support the role of AA in human CHN and provide a useful model for examination of the pathophysiologic pathways of renal fibrosis.
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Rekhtina, I. G., E. V. Kazarina, E. S. Stolyarevich, A. M. Kovrigina, V. N. Dvirnyk, S. M. Kulikov, and L. P. Mendeleeva. "Morphological and immunohistochemical predictors of renal response to therapy patients with myeloma cast nephropathy and dialysis-dependent acute kidney injury." Terapevticheskii arkhiv 92, no. 7 (September 1, 2020): 63–69. http://dx.doi.org/10.26442/00403660.2020.07.000776.
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Aim.Reveal morphological and immunohistochemical predictors of reversibility of dialysis-dependent acute kidney injury (AKI) in patients with myeloma cast nephropathy (MCN) based on the study of kidney biopsy.
Materials and methods.Renal pathological findings were studied in 36 patients with MCN and dialysis-dependent stage 3 AKI (AKIN, 2012). The study of biopsy samples was performed by a semi-quantitative and quantitative analysis using computer morphometry. The expression of E-cadherin, vimentin and-smooth muscle actin was determined immunohistochemically in the tubular cells and interstitium. Induction therapy for 26 patients was carried out to bortezomib-based programs; in 10 patients other schemes were used. A comparative analysis of morphological changes in nephrobiopathy depending on the renal response was performed in patients with achieved hematologic remission.
Results.Improved renal function was observed only in patients with hematologic response to therapy. There were no differences in the number of sclerotic glomeruli, protein casts, the area of inflammatory interstitial infiltration, and the degree of acute tubular damage in patients with and without renal response. In patients with renal response compared with patients without improving renal function, the area of interstitial fibrosis was less (24.9% and 45.9%, respectively;p=0.001), and the area of E-cadherin expression was larger (15.9% and 7.1%, respectively;p=0.006). Interstitial fibrosis of 40% or more and/or the area of expression of E-cadherin less than 10% of the area of tubulo-interstitium have an unfavorable prognostic value in achieving a renal response in MCN.
Conclusion.If the interstitial fibrosis area is 40% or more and the expression area of E-cadherin is less than 10%, the probability of the absence of a renal response is 93.3% (OR=24.5) even when a hematological response to induction therapy is achieved. The number of protein casts, the prevalence of acute tubular damage and inflammatory interstitial infiltration have not prognostic value.
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Tampe, Désirée, Laura Schridde, Peter Korsten, Philipp Ströbel, Michael Zeisberg, Samy Hakroush, and Björn Tampe. "Different Patterns of Kidney Fibrosis Are Indicative of Injury to Distinct Renal Compartments." Cells 10, no. 8 (August 6, 2021): 2014. http://dx.doi.org/10.3390/cells10082014.
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Kidney fibrosis is a common manifestation and hallmark of a wide variety of chronic kidney disease (CKD) that appears in different morphological patterns, suggesting distinct pathogenic causes. Broad macroscopically visible scars are the sequelae of severe focal injury and complete parenchymal destruction, reflecting a wound healing response as a consequence of infarction. In the kidney, chronic glomerular injury leads to atrophy of the corresponding tubule, degeneration of this specific nephron, and finally interstitial fibrosis/tubular atrophy (IF/TA). Compared to this glomerulus-induced focal replacement scar, diffuse fibrosis independent of tubular atrophy appears to be a different pathogenic process. Kidney fibrosis appears to develop in a compartment-specific manner, but whether focal and diffuse fibrosis has distinct characteristics associated with other glomerular or tubulointerstitial lesions remains elusive. In the present study, we aimed to analyze renal fibrotic patterns related to renal lesions, which directly contribute to renal fibrogenesis, to unravel fibrotic patterns and manifestations upon damage to distinct renal compartments. Patterns of kidney fibrosis were analyzed in experimental models of CKD and various renal pathologies in correlation with histopathological and ultrastructural findings. After the induction of isolated crescentic glomerulonephritis (GN) in nephrotoxic serum-nephritis (NTN), chronic glomerular damage resulted in predominantly focal fibrosis adjacent to atrophic tubules. By contrast, using unilateral ureteral obstruction (UUO) as a model of primary injury to the tubulointerstitial compartment revealed diffuse fibrosis as the predominant pattern of chronic lesions. Finally, folic acid-induced nephropathy (FAN) as a model of primary tubular injury with consecutive tubular atrophy independent of chronic glomerular damage equally induced predominant focal IF/TA. By analyzing several renal pathologies, our data also suggest that focal and diffuse fibrosis appear to contribute as chronic lesions in the majority of human renal disease, mainly being present in antineutrophil cytoplasmic antibody (ANCA)-associated GN, lupus nephritis, and IgA nephropathy (IgAN). Focal IF/TA correlated with glomerular damage and irreversible injury to nephrons, whereas diffuse fibrosis in ANCA GN was associated explicitly with interstitial inflammation independent of glomerular damage and nephron loss. Ultrastructural analysis of focal IF/TA versus diffuse fibrosis revealed distinct matrix compositions, further supported by different collagen signatures in transcriptome datasets. With regard to long-term renal outcome, only the extent of focal IF/TA correlated with the development of end-stage kidney disease (ESKD) in ANCA GN. In contrast, diffuse kidney fibrosis did not associate with the long-term renal outcome. In conclusion, we here provide evidence that a focal pattern of kidney fibrosis seems to be associated with nephron loss and replacement scarring. In contrast, a diffuse pattern of kidney fibrosis appears to result from primary interstitial inflammation and injury.
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Sun, Ke, Zhenliang Fan, and Junfeng Fan. "A study on the mechanism of cordycepin in regulating autophagy and alleviating renal tubular interstitial fibrosis." Tropical Journal of Pharmaceutical Research 23, no. 3 (April 14, 2024): 529–35. http://dx.doi.org/10.4314/tjpr.v23i3.6.
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Purpose: To elucidate the role of cordycepin in modulating autophagy and mitigating renal tubular interstitial fibrosis in a rat model of unilateral ureteral obstruction (UUO). Methods: Forty male Sprague-Dawley (SD) rats were assigned to four groups: control, sham, UUO and cordyceps-treated groups (10 rats per group). The UUO and cordyceps groups underwent surgery to induce unilateral ureteral obstruction. The cordyceps group received intravenous cordycepin (10 mg/kg) daily for 14 days, while the control and UUO groups received normal saline. Histopathological examination, assessment of fibrosis markers (α-SMA, collagen III) and autophagy markers (Atg5, LC3II/I) were conducted. Results: The UUO group exhibited significant tubular damage and interstitial fibrosis, with elevated serum levels of pro-inflammatory and oxidative markers (p < 0.05). Cordycepin treatment attenuated these pathological changes, evidenced by reduced fibrosis, inflammation and oxidative stress. Enhanced autophagic activity was observed in the cordycepin group, suggesting a potential mechanism of its renoprotective effect. Conclusion: Cordyceps is effective in inhibiting renal tubulointerstitial fibrosis, potentially through the activation of autophagy and reduction of inflammation and oxidative stress. Future studies should focus on unraveling the specific molecular mechanisms of cordycepin's action and assessing its applicability in CKD treatment.
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Ranganathan, Punithavathi, Calpurnia Jayakumar, and Ganesan Ramesh. "Proximal tubule-specific overexpression of netrin-1 suppresses acute kidney injury-induced interstitial fibrosis and glomerulosclerosis through suppression of IL-6/STAT3 signaling." American Journal of Physiology-Renal Physiology 304, no. 8 (April 15, 2013): F1054—F1065. http://dx.doi.org/10.1152/ajprenal.00650.2012.
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Acute kidney injury-induced organ fibrosis is recognized as a major risk factor for the development of chronic kidney disease, which remains one of the leading causes of death in the developed world. However, knowledge on molecules that may suppress the fibrogenic response after injury is lacking. In ischemic models of acute kidney injury, we demonstrate a new function of netrin-1 in regulating interstitial fibrosis. Acute injury was promptly followed by a rise in serum creatinine in both wild-type and netrin-1 transgenic animals. However, the wild-type showed a slow recovery of kidney function compared with netrin-1 transgenic animals and reached baseline by 3 wk. Histological examination showed increased infiltration of interstitial macrophages, extensive fibrosis, reduction of capillary density, and glomerulosclerosis. Collagen IV and α-smooth muscle actin expression was absent in sham-operated kidneys; however, their expression was significantly increased at 2 wk and peaked at 3 wk after reperfusion. These changes were reduced in the transgenic mouse kidney, which overexpresses netrin-1 in proximal tubular epithelial cells. Fibrosis was associated with increased expression of IL-6 and extensive and chronic activation of STAT3. Administration of IL-6 exacerbated fibrosis in vivo in wild-type, but not in netrin-1 transgenic mice kidney and increased collagen I expression and STAT3 activation in vitro in renal epithelial cells subjected to hypoxia-reoxygenation, which was suppressed by netrin-1. Our data suggest that proximal tubular epithelial cells may play a prominent role in interstitial fibrosis and that netrin-1 could be a useful therapeutic agent for treating kidney fibrosis.
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Huang, Ming, Shuai Zhu, Huihui Huang, Jinzhao He, Kenji Tsuji, William W. Jin, Dongping Xie, et al. "Integrin-Linked Kinase Deficiency in Collecting Duct Principal Cell Promotes Necroptosis of Principal Cell and Contributes to Kidney Inflammation and Fibrosis." Journal of the American Society of Nephrology 30, no. 11 (October 25, 2019): 2073–90. http://dx.doi.org/10.1681/asn.2018111162.
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BackgroundNecroptosis is a newly discovered cell death pathway that plays a critical role in AKI. The involvement of integrin-linked kinase (ILK) in necroptosis has not been studied.MethodsWe performed experiments in mice with an Ilk deletion in collecting duct (CD) principal cells (PCs), and cultured tubular epithelial cells treated with an ILK inhibitor or ILK siRNA knockdown.ResultsIlk deletion in CD PCs resulted in acute tubular injury and early mortality in mice. Progressive interstitial fibrosis and inflammation associated with the activation of the canonical TGF-β signaling cascade were detected in the kidneys of the mice lacking ILK in the CD PCs. In contrast to the minimal apoptosis detected in the animals’ injured CDs, widespread necroptosis was present in ILK-deficient PCs, characterized by cell swelling, deformed mitochondria, and rupture of plasma membrane. In addition, ILK deficiency resulted in increased expression and activation of necroptotic proteins MLKL and RIPK3, and membrane translocation of MLKL in CD PCs. ILK inhibition and siRNA knockdown reduced cell survival in cultured tubular cells, concomitant with increased membrane accumulation of MLKL and/or phospho-MLKL. Administration of a necroptosis inhibitor, necrostatin-1, blocked cell death in vitro and significantly attenuated inflammation, interstitial fibrosis, and renal failure in ILK-deficient mice.ConclusionsThe study demonstrates the critical involvement of ILK in necroptosis through modulation of the RIPK3 and MLKL pathway and highlights the contribution of CD PC injury to the development of inflammation and interstitial fibrosis of the kidney.
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Wang, Xiaohua, Yang Zhou, Ruoyun Tan, Mingxia Xiong, Weichun He, Li Fang, Ping Wen, Lei Jiang, and Junwei Yang. "Mice lacking the matrix metalloproteinase-9 gene reduce renal interstitial fibrosis in obstructive nephropathy." American Journal of Physiology-Renal Physiology 299, no. 5 (November 2010): F973—F982. http://dx.doi.org/10.1152/ajprenal.00216.2010.
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Matrix metalloproteinase-9 (MMP-9) is one of the major components of the matrix proteolytic network, and its role in the pathogenesis of renal interstitial fibrosis remains largely unknown. Here, we demonstrate that ablation of MMP-9 attenuated renal interstitial fibrotic lesions in obstructive nephropathy. Mice lacking MMP-9 were less likely to develop morphological injury, which was characterized by a reduced disruption of tubular basement membrane (TBM) and expression of fibronectin as well as deposition of total tissue collagen in the kidneys after sustained ureteral obstruction compared with their wild-type counterparts. Deficiency of MMP-9 blocked tubular epithelial-to-myofibroblast transition (EMT) but did not alter the induction of transforming growth factor (TGF)-β1 axis expression in the obstructed kidneys. In vitro, TBM, which was digested by MMP-9 instead of MMP-9 itself, induces EMT and enhances migration of transformed cells. Thus increased MMP-9 is detrimental in renal interstitial fibrogenesis through a cascade of events that leads to TBM destruction and in turn to promotion of EMT. Our findings establish a crucial and definite importance of MMP-9 in the pathogenesis of renal interstitial fibrosis at the whole-animal level.
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Gui, Yuan, and Chunsun Dai. "mTOR Signaling in Kidney Diseases." Kidney360 1, no. 11 (September 3, 2020): 1319–27. http://dx.doi.org/10.34067/kid.0003782020.
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The mammalian target of rapamycin (mTOR), a serine/threonine protein kinase, is crucial in regulating cell growth, metabolism, proliferation, and survival. Under physiologic conditions, mTOR signaling maintains podocyte and tubular cell homeostasis. In AKI, activation of mTOR signaling in tubular cells and interstitial fibroblasts promotes renal regeneration and repair. However, constitutive activation of mTOR signaling in kidneys results in the initiation and progression of glomerular hypertrophy, interstitial fibrosis, polycystic kidney disease, and renal cell carcinoma. Here, we summarize the recent studies about mTOR signaling in renal physiology and injury, and discuss the possibility of its use as a therapeutic target for kidney diseases.
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Yamashita, Noriyuki, Tetsuro Kusaba, Tomohiro Nakata, Aya Tomita, Tomoharu Ida, Noriko Watanabe-Uehara, Kisho Ikeda, et al. "Intratubular epithelial-mesenchymal transition and tubular atrophy after kidney injury in mice." American Journal of Physiology-Renal Physiology 319, no. 4 (October 1, 2020): F579—F591. http://dx.doi.org/10.1152/ajprenal.00108.2020.
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Tubular atrophy is a common pathological feature of kidney fibrosis. Although fibroblasts play a predominant role in tissue fibrosis, the role of repairing tubular epithelia in tubular atrophy is unclear. We demonstrated the essential role of focal adhesion kinase (FAK)-mediated intratubular epithelial-mesenchymal transition (EMT) in the pathogenesis of tubular atrophy after severe ischemia-reperfusion injury (IRI). Actively proliferating tubular epithelia undergoing intratubular EMT were noted in the acute phase of severe IRI, resulting in tubular atrophy in the chronic phase, reflecting failed tubular repair. Furthermore, FAK was phosphorylated in the tubular epithelia in the acute phase of severe IRI, and its inhibition ameliorated both tubular atrophy and interstitial fibrosis in the chronic phase after injury. In vivo clonal analysis of single-labeled proximal tubular epithelial cells after IRI using proximal tubule reporter mice revealed substantial clonal expansion after IRI, reflecting active epithelial proliferation during repair. The majority of these proliferating epithelia were located in atrophic and nonfunctional tubules, and FAK inhibition was sufficient to prevent tubular atrophy. In vitro, transforming growth factor-β induced FAK phosphorylation and an EMT phenotype, which was also prevented by FAK inhibition. In an in vitro tubular epithelia gel contraction assay, transforming growth factor-β treatment accelerated gel contraction, which was suppressed by FAK inhibition. In conclusion, injury-induced intratubular EMT is closely related to tubular atrophy in a FAK-dependent manner.
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Kida, Yujiro, Kinji Asahina, Hirobumi Teraoka, Inna Gitelman, and Tetsuji Sato. "Twist Relates to Tubular Epithelial-Mesenchymal Transition and Interstitial Fibrogenesis in the Obstructed Kidney." Journal of Histochemistry & Cytochemistry 55, no. 7 (March 19, 2007): 661–73. http://dx.doi.org/10.1369/jhc.6a7157.2007.
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Epithelial-mesenchymal transition (EMT) is a critical step in renal fibrosis. It has been recently reported that a transcription factor, Twist, plays a pivotal role in metastasis of breast tumors by inducing EMT. In this study, we examined whether Twist relates to renal fibrogenesis including EMT of tubular epithelia, evaluating Twist expression level in the unilateral ureteral obstruction (UUO) model. Kidneys of mice subjected to UUO were harvested 1, 3, 7, and 10 days after obstruction. Compared with control kidneys, Twist mRNA-level significantly increased 3 days after UUO (UUO day 3 kidney) and further augmented until 10 days after UUO. Twist expression increased in tubular epithelia of the dilated tubules and the expanded interstitial areas of UUO kidneys, where cell-proliferating appearances were frequently found in a time-dependent manner. Although a part of tubular cells in whole nephron segment were immunopositive for Twist in UUO day 7 kidneys, tubular epithelia downstream of nephron more frequently expressed Twist than upstream of nephron. In UUO day 7 kidneys, some tubular epithelia were confirmed to coexpress Twist and fibroblast-specific protein-1, a marker for EMT, indicating that Twist is involved in tubular EMT under pathological state. Twist was expressed also in a number of α-smooth muscle actin-positive myofibroblasts located in the expanded interstitial area of UUO kidneys. From these findings, the present investigation suggests that Twist is associated with tubular EMT, proliferation of myofibroblasts, and subsequent renal fibrosis in obstructed kidneys.
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Ginley, Brandon, Kuang-Yu Jen, Seung Seok Han, Luís Rodrigues, Sanjay Jain, Agnes B. Fogo, Jonathan Zuckerman, et al. "Automated Computational Detection of Interstitial Fibrosis, Tubular Atrophy, and Glomerulosclerosis." Journal of the American Society of Nephrology 32, no. 4 (February 23, 2021): 837–50. http://dx.doi.org/10.1681/asn.2020050652.
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BackgroundInterstitial fibrosis, tubular atrophy (IFTA), and glomerulosclerosis are indicators of irrecoverable kidney injury. Modern machine learning (ML) tools have enabled robust, automated identification of image structures that can be comparable with analysis by human experts. ML algorithms were developed and tested for the ability to replicate the detection and quantification of IFTA and glomerulosclerosis that renal pathologists perform.MethodsA renal pathologist annotated renal biopsy specimens from 116 whole-slide images (WSIs) for IFTA and glomerulosclerosis. A total of 79 WSIs were used for training different configurations of a convolutional neural network (CNN), and 17 and 20 WSIs were used as internal and external testing cases, respectively. The best model was compared against the input of four renal pathologists on 20 new testing slides. Further, for 87 testing biopsy specimens, IFTA and glomerulosclerosis measurements made by pathologists and the CNN were correlated to patient outcome using classic statistical tools.ResultsThe best average performance across all image classes came from a DeepLab version 2 network trained at 40× magnification. IFTA and glomerulosclerosis percentages derived from this CNN achieved high levels of agreement with four renal pathologists. The pathologist- and CNN-based analyses of IFTA and glomerulosclerosis showed statistically significant and equivalent correlation with all patient-outcome variables.ConclusionsML algorithms can be trained to replicate the IFTA and glomerulosclerosis assessment performed by renal pathologists. This suggests computational methods may be able to provide a standardized approach to evaluate the extent of chronic kidney injury in situations in which renal-pathologist time is restricted or unavailable.
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Hart, Allyson, Scott Jackson, Bertram L. Kasiske, Michael S. Mauer, Behzad Najafian, Arthur J. Matas, Richard Spong, and Hassan N. Ibrahim. "Uric Acid and Allograft Loss From Interstitial Fibrosis/Tubular Atrophy." Transplantation 97, no. 10 (May 2014): 1066–71. http://dx.doi.org/10.1097/01.tp.0000440952.29757.66.
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Wilson, Parker C., Michael Kashgarian, and Gilbert Moeckel. "Interstitial inflammation and interstitial fibrosis and tubular atrophy predict renal survival in lupus nephritis." Clinical Kidney Journal 11, no. 2 (August 31, 2017): 207–18. http://dx.doi.org/10.1093/ckj/sfx093.
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Morales, Enrique, Hernando Trujillo, Teresa Bada, Marina Alonso, Eduardo Gutiérrez, Esther Rodríguez, Elena Gutiérrez, María Galindo, and Manuel Praga. "What is the value of repeat kidney biopsies in patients with lupus nephritis?" Lupus 30, no. 1 (October 20, 2020): 25–34. http://dx.doi.org/10.1177/0961203320965703.
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Introduction Recent studies with protocol biopsies have shown a mismatch between clinical and histological remission in lupus nephritis (LN). We aimed to evaluate histological changes in repeat kidney biopsies by clinical indication in patients with LN. Methods We analyzed 107 patients with LN in which a kidney biopsy was performed between 2008 and 2018. Of those, we included 26 (24.2%) who had ≥2 kidney biopsies. Classification was done according to the International Society of Nephrology/Renal Pathology Society. Results Mean time between biopsies was 71.5 ± 10.7 months. 73.1% of patients presented a change of class at repeat biopsy; 38.4% to a higher class and 34.6% to a lower class. A significant increase in glomerulosclerosis (% GS) (3.8% vs 18.7%, p = 0.006), interstitial fibrosis (3.8% vs 26.9%, p = 0.021), tubular atrophy (15.4% vs 57.7%, p = 0.001) and chronicity index (CI) (1 vs 3, p < 0.001) was observed at repeat biopsy. Subjects who developed chronic kidney disease progression had a lower rate of complete remission at 12 months (0% vs 37.5%, p = 0.02), higher % GS at first biopsy (7.9% vs 1.2%, p = 0.02) and higher CI (4 vs 2, p = 0.006), tubular atrophy (90% vs 37.6%, p = 0.008), interstitial fibrosis (50% vs 12.5%, p = 0.036) and vascular lesions (60% vs 18.8%, p = 0.031) at second biopsy. Conclusions Our major finding was that patients with LN showed a significant increase in % GS, interstitial fibrosis, tubular atrophy and vascular lesions in repeat biopsies performed by clinical indication. This suggest that a second kidney biopsy may provide valuable and useful information regarding kidney disease progression.
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Cahyawati, Putu Nita, Ngatidjan ., Dwi Cahyani Ratna Sari, Muhammad Mansyur Romi, Nur Arfian, Muhammad Mansyur Romi, Muhammad Mansyur Romi, Nur Arfian, and Nur Arfian. "SIMVASTATIN ATTENUATES RENAL FAILURE IN MICE WITH A 5/6 SUBTOTAL NEPHRECTOMY." International Journal of Pharmacy and Pharmaceutical Sciences 9, no. 5 (May 1, 2017): 12. http://dx.doi.org/10.22159/ijpps.2017v9i5.12261.
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Objective: The objective of this study to investigate the effect of simvastatin on kidney fibrosis in mice with a 5/6 subtotal nephrectomy.Methods: Thirty adults (3 mo old) male Swiss mice were submitted to a 5/6 subtotal nephrectomy and studied after 14 d. Animals were divided into five groups: 5/6 subtotal nephrectomy (SN, n=6), sham operation (SH, n=6), simvastatin 5.2 mg/kg body weight (SIM-1, n=6), simvastatin 10.4 mg/kg body weight (SIM-2, n=6), and simvastatin 20.8 mg/kg body weight (SIM-3, n=6) groups. At sacrifice, kidneys were harvested for morphology (glomerulosclerosis (GS), tubular injury and interstitial fibrosis), immunostaining (α-smooth muscle actin (α-SMA)) and platelet-derived growth factor receptor beta (PDGF-Rβ) and reverse transcriptase-polymerase chain reaction (RT-PCR) (MCP-1, ICAM-1, nephrin, and podocin) analysis.Results: Glomerulosclerosis, tubular injury and interstitial fibrosis in the simvastatin group was significantly lower than SN group (p<0.05). Simvastatin significantly reduced α-SMA expression (3.61±1.06 vs 7.91±1.26, p<0.05, SIM-1 vs SN; 2.86±0.61 vs 7.91±1.26, p<0.05, SIM-2 vs SN; 1.71±0.50 vs 7.91±1.26, p<0.05, SIM-3 vs SN), MCP-1 was markedly expressed in the 5/6 subtotal nephrectomy kidneys and was reduced with simvastatin (1.4±0.64 vs 0.57±0.23, p<0.05, SN vs SIM-1; 1.4±0.64 vs 0.6±0.26, p<0.05, SN vs SIM-2; 1.4±0.64 vs 0.52±0.21, SN vs SIM-3, p<0.05). Simvastatin did not increase nephrin expression, but it increased podocin expression significantly in the SIM-3 group.Conclusion: Simvastatin significantly attenuated GS, tubular injury and interstitial fibrosis through the downregulation of myofibroblast expansion and inflammatory mediators in mice with a 5/6 subtotal nephrectomy.
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Cui, Wenpeng, Hasiyeti Maimaitiyiming, Xinyu Qi, Heather Norman, Qi Zhou, Xiaojun Wang, Jian Fu, and Shuxia Wang. "Increasing cGMP-dependent protein kinase activity attenuates unilateral ureteral obstruction-induced renal fibrosis." American Journal of Physiology-Renal Physiology 306, no. 9 (May 1, 2014): F996—F1007. http://dx.doi.org/10.1152/ajprenal.00657.2013.
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Our previous studies support the protective effect of cGMP and cGMP-dependent protein kinase I (PKG-I) pathway on the development of renal fibrosis. Therefore, in the present studies, we determined whether pharmacologically or genetically increased PKG activity attenuates renal fibrosis in a unilateral ureteral obstruction (UUO) model and also examined the mechanisms involved. To increase PKG activity, we used the phosphodiesterase 5 inhibitor sildenafil and PKG transgenic mice. UUO model was induced in wild-type or PKG-I transgenic mice by ligating the left lateral ureteral and the renal fibrosis was observed after 14 days of ligation. Sildenafil was administered into wild-type UUO mice for 14 days. In vitro, macrophage and proximal tubular cell function was also analyzed. We found that sildenafil treatment or PKG transgenic mice had significantly reduced UUO-induced renal fibrosis, which was associated with reduced TGF-β signaling and reduced macrophage infiltration into kidney interstitial. In vitro data further demonstrated that both macrophages and proximal tubular cells were important sources of UUO-induced renal TGF-β levels. The interaction between macrophages and tubular cells contributes to TGF-β-induced renal fibrosis. Taken together, these data suggest that increasing PKG activity ameliorates renal fibrosis in part through regulation of macrophage and tubular cell function, leading to reduced TGF-β-induced fibrosis.
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Yao, Lan, M. Frances Wright, Brandon C. Farmer, Laura S. Peterson, Amir M. Khan, Jianyong Zhong, Leslie Gewin, Chuan-Ming Hao, Hai-Chun Yang, and Agnes B. Fogo. "Fibroblast-specific plasminogen activator inhibitor-1 depletion ameliorates renal interstitial fibrosis after unilateral ureteral obstruction." Nephrology Dialysis Transplantation 34, no. 12 (April 10, 2019): 2042–50. http://dx.doi.org/10.1093/ndt/gfz050.
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Abstract Background Plasminogen activator inhibitor-1 (PAI-1) expression increases extracellular matrix deposition and contributes to interstitial fibrosis in the kidney after injury. While PAI-1 is ubiquitously expressed in the kidney, we hypothesized that interstitial fibrosis is strongly dependent on fibroblast-specific PAI-1 (fbPAI-1). Methods Tenascin C Cre (TNC Cre) and fbPAI-1 knockdown (KD) mice with green fluorescent protein (GFP) expressed within the TNC construct underwent unilateral ureteral obstruction and were sacrificed 10 days later. Results GFP+ cells in fbPAI-1 KD mice showed significantly reduced PAI-1 expression. Interstitial fibrosis, measured by Sirius red staining and collagen I western blot, was significantly decreased in fbPAI-1 KD compared with TNC Cre mice. There was no significant difference in transforming growth factor β (TGF-β) expression or its activation between the two groups. However, GFP+ cells from fbPAI-1 KD mice had lower TGF β and connective tissue growth factor (CTGF) expression. The number of fibroblasts was decreased in fbPAI-1 KD compared with TNC Cre mice, correlating with decreased alpha smooth muscle actin (α-SMA) expression and less fibroblast cell proliferation. TNC Cre mice had decreased E-cadherin, a marker of differentiated tubular epithelium, in contrast to preserved expression in fbPAI-1 KD. F4/80-expressing cells, mostly CD11c+/F4/80+ cells, were increased while M1 macrophage markers were decreased in fbPAI-1 KD compared with TNC Cre mice. Conclusion These findings indicate that fbPAI-1 depletion ameliorates interstitial fibrosis by decreasing fibroblast proliferation in the renal interstitium, with resulting decreased collagen I. This is linked to decreased M1 macrophages and preserved tubular epithelium.
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Fine, L. G., and J. T. Norman. "Renal growth responses to acute and chronic injury: routes to therapeutic intervention." Journal of the American Society of Nephrology 2, no. 10 (April 1992): S206. http://dx.doi.org/10.1681/asn.v210s206.
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Knowledge of the control of cell growth and extracellular matrix deposition has assumed center stage in the understanding of how the diseased kidney responds to injury. After acute tubular injury, there may be reversible, partial depolarization of renal cells or cell necrosis. The latter requires a regenerative response, which could be under the control of growth factors such as epidermal growth factor (EGF). Up-regulation of EGF receptors on viable cells provides the cell with an enhanced growth response despite a reduction in EGF production by the kidney. Acute glomerular injury involves a highly complex network of cytokines and growth inhibitors, the most important of which appear to be platelet-derived growth factor as a mitogen and transforming growth factor beta as an activator of extracellular matrix deposition. The long-term growth responses of the kidney to injury, reflected by chronic renal diseases, include tubular hypertrophy in those nephrons which are less affected by the primary disease. Tubular cell enlargement appears to proceed along a pathway that is different from the growth in cell size which precedes cell division, at least as indicated by a fundamentally different pattern of early gene expression. This pattern is not suggestive of a classical growth factor-initiated process. Other chronic changes that seem to correlate well with the progression of human disease are tubular atrophy and interstitial fibrosis. Growth factors produced by tubular cells may cause proliferation and matrix deposition by adjacent interstitial fibroblasts. A scheme is proposed in which low-grade ischemic injury to tubular cells, secondary to microvascular injury, leads to tubular atrophy, the release of growth factors, interstitial fibrosis, and the obliteration of peritubular capillaries. This would aggravate primary glomerular injury by compromising the vascular outflow from the glomerulus and would account for the long-recognized association between tubulo-interstitial injury and the progression of a variety of renal diseases. The use of growth factors to stimulate specific growth responses, antibodies, or inhibitory molecules to inhibit scarring generated by cytokines and the potential for genetic manipulation of the kidney provide future avenues for manipulating the growth response of the diseased kidney.
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Yang, Junwei, and Youhua Liu. "Delayed administration of hepatocyte growth factor reduces renal fibrosis in obstructive nephropathy." American Journal of Physiology-Renal Physiology 284, no. 2 (February 1, 2003): F349—F357. http://dx.doi.org/10.1152/ajprenal.00154.2002.
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Hepatocyte growth factor (HGF) is a renotropic protein that elicits antifibrogenic activity by preventing the activation of matrix-producing myofibroblast cells in animal models of chronic renal diseases. However, whether a delayed administration of HGF can still attenuate renal fibrosis remains uncertain. In this study, we examined the therapeutic potential of exogenous HGF on an established renal interstitial fibrosis induced by unilateral ureteral obstruction (UUO). Three days after UUO, the obstructed kidneys displayed interstitial fibrotic lesions with characteristic features of an established renal fibrosis, as manifested by myofibroblast activation, fibronectin overexpression, interstitial matrix deposition, and transforming growth factor-β1 upregulation. Beginning at this time point, administration of recombinant HGF into mice by intravenous injections for 11 days markedly suppressed the progression of renal interstitial fibrosis. HGF significantly suppressed renal α-smooth muscle actin expression, total kidney collagen contents, interstitial matrix components, such as fibronectin, and renal expression of transforming growth factor-β1 and its type I receptor. Compared with the starting point (3 days after UUO), HGF treatment largely blunted the progression of myofibroblast accumulation and collagen deposition but did not reverse it. Delayed administration of HGF also suppressed the myofibroblastic transdifferentiation from tubular epithelial cells in vitro, as demonstrated by a decline in α-smooth muscle actin and fibronectin expression. These results suggest that exogenous HGF exhibits potent therapeutic effects on retarding the progression of an established renal fibrosis.
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Torsello, Barbara, Sofia De Marco, Silvia Bombelli, Ingrid Cifola, Ivana Morabito, Lara Invernizzi, Chiara Meregalli, et al. "High glucose induces an activated state of partial epithelial-mesenchymal transition in human primary tubular cell cultures." PLOS ONE 18, no. 2 (February 24, 2023): e0279655. http://dx.doi.org/10.1371/journal.pone.0279655.
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Tubulointerstitial fibrosis is observed in diabetic nephropathy. It is still debated whether tubular cells, undergoing epithelial-mesenchymal transition (EMT) in high glucose (HG) conditions, may contribute to interstitial fibrosis development. In this study, we investigated the phenotypic and molecular EMT-like changes and the alteration of inflammatory and fibrogenic secretome induced by HG in human primary tubular cell cultures. Taking advantage of this in vitro cell model composed of proximal and distal tubular cells, we showed that HG-treated tubular cells acquired a fibroblast-like morphology with increased cytoplasmic stress fibers, maintaining the expression of the epithelial markers specific of proximal and distal tubular cells. HG increased Snail1, miRNA210 and Vimentin mesenchymal markers, decreased N-cadherin expression and migration ability of primary tubular cells, while E-cadherin expression and focal adhesion distribution were not affected. Furthermore, HG treatment of tubular cells altered the inflammatory cytokine secretion creating a secretome able to enhance the proliferation and migration of fibroblasts. Our findings show that HG promotes an activated state of partial EMT in human tubular primary cells and induces a pro-inflammatory and pro-fibrogenic microenvironment, supporting the active role of tubular cells in diabetic nephropathy onset.
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Eddy, A. A. "Molecular insights into renal interstitial fibrosis." Journal of the American Society of Nephrology 7, no. 12 (December 1996): 2495–508. http://dx.doi.org/10.1681/asn.v7122495.
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Progressive interstitial fibrosis accompanied by loss of renal tubules and interstitial capillaries typifies all progressive renal diseases. Dynamic and complex, the process evidently overlaps with matrix remodeling; it may even be reversible. The interstitial fibrous tissue comprises several normal and novel matrix proteins, proteoglycans, and glycoproteins. Interstitial myofibroblasts are a major site of matrix protein overproduction, although resident fibroblasts, tubular cells, and inflammatory cells may contribute. Inadequate matrix degradation also appears to contribute to the fibrogenic process. Two protease cascades, the metalloproteinases and the plasminogen activator/ plasmin family of serine proteases, are implicated in the turnover of interstitial matrix proteins; upregulated expression of protease inhibitors has been observed in each. Increased tissue inhibitor of metalloproteinase-1 and plasminogen activator inhibitor-1 levels suggest that the intrinsic renal activity of the metalloproteinases and serine proteases are inhibited while matrix proteins accumulate in the interstitium. Several signals that may direct the interstitial fibrogenic process have been identified, but not yet proved to cause it. Upregulated expression of transforming growth factor beta-1, the proteotypic fibrogenic cytokine, has been observed in experimental and human models; it probably does not act alone. There may be supportive roles for platelet-derived growth factor, interleukin-1, basic fibroblast growth factor, angiotensin II, and endothelin-1. Although it is not known why interstitial fibrosis compromises renal function, atrophy of renal tubules may be pivotal. Ischemic necrosis and/or apoptosis may generate nonfunctioning atubular and sclerotic glomeruli. Future studies must delineate the molecular basis of the differences between renal repair and renal destruction by fibrosis, two processes that share many common features.
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Ma, Frank Y., Jian Liu, A. Richard Kitching, Carl L. Manthey, and David J. Nikolic-Paterson. "Targeting renal macrophage accumulation via c-fms kinase reduces tubular apoptosis but fails to modify progressive fibrosis in the obstructed rat kidney." American Journal of Physiology-Renal Physiology 296, no. 1 (January 2009): F177—F185. http://dx.doi.org/10.1152/ajprenal.90498.2008.
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The role of macrophages in promoting interstitial fibrosis in the obstructed kidney is controversial. Macrophage depletion studies in the unilateral ureter obstruction (UUO) model have produced opposing results, presumably reflecting the subtleties of the individual depletion methods used. To address this question, we targeted the macrophage colony-stimulating factor receptor, c- fms, which is uniquely expressed by cells of the monocyte/macrophage lineage. Administration of 5, 12.5, or 30 mg/kg (bid) of a selective inhibitor of c- fms kinase activity (fms-I) resulted in a dose-dependent inhibition of renal macrophage accumulation in the rat UUO model. This was due to inhibition of local macrophage proliferation in the obstructed kidney and, at higher doses, to depletion of circulating blood monocytes. To determine the contribution of macrophages to renal pathology in the obstructed kidney, groups of animals were treated with 30 mg/kg fms-I and killed 3, 7, or 14 days later. Complete inhibition of renal macrophage accumulation prevented upregulation of the macrophage-associated proinflammatory mediators, tumor necrosis factor (TNF)-α and matrix metalloproteinase-12, and significantly reduced tubular apoptosis. Macrophage depletion caused a minor reduction of interstitial myofibroblast accumulation and deposition of interstitial collagen IV at day 3, but no difference was seen in renal fibrosis on day 7 or 14. Similarly, the upregulation of collagen IV, fibronectin, transforming growth factor-β1 and connective tissue growth factor mRNA levels on day 7 and 14 in the obstructed kidney was unaffected by macrophage depletion. In conclusion, c- fms blockade was shown to selectively prevent interstitial macrophage accumulation and to reduce tubular apoptosis in the obstructed kidney, but it had no significant impact on the development of interstitial fibrosis.