Renal Fibroblasts and Myofibroblasts in Chronic Kidney Disease

Strutz, Frank; Zeisberg, Michael

doi:10.1681/asn.2006050420

Cited by 292 publications

(275 citation statements)

References 61 publications

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“…During tubulointerstitial fibrosis, renal fibroblasts maintain their activated phenotype (myofibroblasts), even after the removal of the initial insult (2,41). Following recurrent tissue injury, myofibroblasts undergo reactivation (42,43).…”

Section: Discussionmentioning

confidence: 99%

Selective delivery of IFN‐γ to renal interstitial myofibroblasts: a novel strategy for the treatment of renal fibrosis

et al. 2014

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Renal fibrosis leads to end-stage renal disease demanding renal replacement therapy because no adequate treatment exists. IFN-g is an antifibrotic cytokine that may attenuate renal fibrosis. Systemically administered IFN-g causes side effects that may be prevented by specific drug targeting. Interstitial myofibroblasts are the effector cells in renal fibrogenesis. Here, we tested the hypothesis that cell-specific delivery of IFN-g to plateletderived growth factor receptor b (PDGFRb)-expressing myofibroblasts attenuates fibrosis in an obstructive nephropathy [unilateral ureteral obstruction (UUO)] mouse model. PEGylated IFN-g conjugated to PDGFRbrecognizing peptide [(PPB)-polyethylene glycol (PEG)-IFN-g] was tested in vitro and in vivo for antifibrotic properties and compared with free IFN-g. PDGFRb expression was >3-fold increased (P < 0.05) in mouse fibrotic UUO kidneys and colocalized with a-smooth muscle actin-positive (SMA + ) myofibroblasts.

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Section: Discussionmentioning

confidence: 99%

Selective delivery of IFN‐γ to renal interstitial myofibroblasts: a novel strategy for the treatment of renal fibrosis

et al. 2014

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“…While these activated myofibroblasts are thought of as key effector cells in the pathogenesis of renal fibrosis, it is clear that they originate from multiple lineages. Accumulating evidence suggests that local interstitial fibroblasts [38], pericytes [39], local mesenchymal stem cells [40] or the injured epithelium itself [10] may contribute to this pool, and there is considerable debate for and against a role of EMT in renal fibrosis [41]. The established criteria supporting a role of EMT in fibrosis are based on the identification of morphological changes and altered levels of key epithelial/mesenchymal markers.…”

Section: Discussionmentioning

confidence: 99%

TGFβ modulates cell-to-cell communication in early epithelial-to-mesenchymal transition

et al. 2012

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Aims/hypothesis A key pathology in diabetic nephropathy is tubulointerstitial fibrosis. The condition is characterised by increased deposition of the extracellular matrix, fibrotic scar formation and declining renal function, with the prosclerotic cytokine TGF-β1 mediating many of these catastrophic changes. Here we investigated whether TGF-β1-induced epithelial-to-mesenchymal transition (EMT) plays a role in alterations in cell adhesion, cell coupling and cell communication in the human renal proximal tubule. Methods Whole-cell and cell compartment abundance of E-cadherin, N-cadherin, snail, vimentin, β-catenin and connexin-43 was determined in human kidney cell line (HK)2 and human proximal tubule cells with or without TGF-β1, using western blotting and immunocytochemistry, followed by quantification by densitometry. The contribution of connexin-43 in proximal tubule cell communication was quantified using small interfering RNA knockdown, while dye-transfer was used to assess gap junctional intercellular communication (GJIC). Functional tethering was assessed by single-cell force spectroscopy with or without TGF-β1, or by immunoneutralisation of cadherin ligation. Results High glucose (25 mmol/l) increased the secretion of TGF-β1 from HK2 cells. Analysis confirmed early TGF-β1-induced morphological and phenotypical changes of EMT, with altered levels of adhesion and adherens junction proteins. These changes correlated with impaired cell adhesion and decreased tethering between coupled cells. Impaired E-cadherin-mediated adhesion reduced connexin-43 production and GJIC, these effects being mimicked by neutralisation of Ecadherin ligation. Upregulation of N-cadherin failed to restore adhesion or connexin-43-mediated GJIC. Conclusions/interpretation We provide compelling evidence that TGF-β1-induced EMT instigates a loss of Ecadherin, cell adhesion and ultimately of connexinmediated cell communication in the proximal tubule under diabetic conditions; these changes occur ahead of overt signs of renal damage.

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“…15,16 Failure of clearance of the fibroblasts after resolution of the initial insults will lead to the persistence of renal fibrogenesis and the resultant tubulointerstitial fibrosis. 17 Human renal interstitial fibroblasts constitutively express Fas and are susceptible to Fas-induced apoptosis. 19 Hayashi et al 18 found that TNFRSF6B offers a survival benefit to synovial fibroblasts in terms of protection against cytotoxic and regulatory effects of Fas.…”

Section: Discussionmentioning

confidence: 99%

“…Otherwise, excessive deposition of extracellular matrix supervenes and leads to eventual renal fibrosis. 17 Anti-apoptotic effect of TNFRSF6B has been shown to decrease elimination of rheumatoid synovial fibroblasts by blocking the interaction with Fas ligand. 18 Fas is normally expressed in human renal interstitial fibroblasts 19 and we hypothesize that TNFRSF6B could involve in the renal fibrogenesis.…”

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confidence: 99%

Expression of TNFRSF6B in kidneys is a novel predictor for progression of chronic kidney disease

Tseng

Yang

et al. 2013

Modern Pathology

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TNFRSF6B overexpression in tumors is a novel predictor for poor prognosis in various cancers; however, whether TNFRSF6B could be expressed in kidney tissues of patients with chronic kidney disease is unknown. Current established risk factors cannot fully predict the progression of chronic kidney disease, and, therefore, it is mandatory to develop a newer marker for predicting disease progression. We conducted a prospective cohort study comprised 167 patients with chronic kidney disease undergoing renal biopsy at a tertiary hospital with median follow-up of 30.5 months. Computer-assisted quantitative immunohistochemical staining analysis of TNFRSF6B in kidney tissues, the expression of a-smooth muscle actin and percentage of fibrosis in renal interstitium, estimated glomerular filtration rate, and urinary protein excretion rate were investigated. Study endpoint was a doubling of serum creatinine and/or end-stage renal failure requiring renal replacement therapy. We found that TNFRSF6B was predominantly expressed in the tubular epithelial cells of renal cortex. The higher the expression of TNFRSF6B, the more the expression of a-smooth muscle actin and fibrosis in interstitium (Po0.001). Forty patients reaching endpoint had lower baseline estimated glomerular filtration rate and higher expression of TNFRSF6B in renal tubular epithelial cells. Multivariate Cox regression analysis showed that high expression of TNFRSF6B independently predicted the risk toward the renal endpoint with a hazard ratio of 3.46 (95% confidence interval (CI) 1.76-6.80, Po0.001) by adjusting for clinical and pathologic variables. While added to a model of estimated glomerular filtration rate, proteinuria and other conventional risk factors, TNFRSF6B further significantly improved the model predictability for progression of chronic kidney disease (area under the curve, 0.82). In conclusion, TNFRSF6B is associated with renal fibrosis and high expression of TNFRSF6B is a novel biomarker for predicting the progression of chronic kidney disease. Modern Pathology (2013) 26, 984-994;

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Renal Fibroblasts and Myofibroblasts in Chronic Kidney Disease

Cited by 292 publications

References 61 publications

Selective delivery of IFN‐γ to renal interstitial myofibroblasts: a novel strategy for the treatment of renal fibrosis

Selective delivery of IFN‐γ to renal interstitial myofibroblasts: a novel strategy for the treatment of renal fibrosis

TGFβ modulates cell-to-cell communication in early epithelial-to-mesenchymal transition

Expression of TNFRSF6B in kidneys is a novel predictor for progression of chronic kidney disease

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