Diabetic Nephropathy: Mechanisms of Renal Disease Progression

Kanwar, Yashpal S.; Wada, Jun; Sun, Lin; Xie, Ping; Wallner, Elisabeth I.; Chen, Sheldon; Chugh, Sumant S.; Danesh, Farhad R.

doi:10.3181/0705-mr-134

Cited by 539 publications

(468 citation statements)

References 61 publications

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“…The ability to switch phenotype stems from a unique plasticity of epithelial cells that has, up until recently, been universally accepted as the sole driving force behind the generation of interstital fibroblasts in kidney disease. EMT of proximal tubule cells (PTC) has been clearly documented in DN, with overwhelming evidence implicating the cytokine Transforming Growth Factor-beta 1 (TGF-β1) as the key mediator [15][16]. Our knowledge of the pathology of TGF-β1 in the kidney is extensive however, the majority of this research is dedicated to exploring the consequences of TGF-β1 signalling in glomerular cells, mesangial cells or podocytes.…”

Section: Introductionmentioning

confidence: 99%

The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy

Hills

Squires

2011

Cytokine & Growth Factor Reviews

173

187

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Transforming Growth Factor-beta (TGF-β) is a pro-sclerotic cytokine widely associated with the development of fibrosis in diabetic nephropathy. Central to the underlying pathology of tubulointerstitial fibrosis is epithelial-to-mesenchymal transition (EMT), or the trans-differentiation of tubular epithelial cells into myofibroblasts. This process is accompanied by a number of key morphological and phenotypic changes culminating in detachment of cells from the tubular basement membrane and migration into the interstitium. Ultimately these cells reside as activated myofibroblasts and further exacerbate the state of fibrosis. A large body of evidence supports a role for TGF-β and downstream Smad signaling in the development and progression of renal fibrosis. Here we discuss a role for TGF-β as the principle effector in the development of renal fibrosis in diabetic nephropathy, focusing on the role of the TGF-β1 isoform and its downstream signaling intermediates, the Smad proteins. Specifically we review evidence for TGF-β1 induced EMT in both the proximal and distal regions of the nephron and describe potential therapeutic strategies that may target TGF-β1 activity.

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Section: Introductionmentioning

confidence: 99%

The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy

Hills

Squires

2011

Cytokine & Growth Factor Reviews

173

187

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“…Overexpression of the ECM components (FN and ColIV) and TGF-b1 has been previously implicated in the development of the renal fibrosis of DN. 18 FN, the first dimeric glycoprotein found in ECM with a molecular weight of 550 kD, contains five spherical functional domains that can bind heparin, collagen, and cell surface receptors. Because of its binding capacity, FN links ECM with the intracellular cytoskeleton and provides trestle structure for other ECM components.…”

Section: Effects Of Nctd On Can/nfatc Signaling Pathway In Hk-2 Cellsmentioning

confidence: 99%

Norcantharidin inhibits the expression of extracellular matrix and TGF-β1 in HK-2 cells induced by high glucose independent of calcineurin signal pathway

Chen

Liu

et al. 2011

Laboratory Investigation

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Norcantharidin (NCTD) was shown in our previous studies to attenuate renal tubulointerstitial fibrosis in rat models with diabetic nephropathy (DN). The aim of this study was to determine the effects of NCTD on the expression of extracellular matrix (ECM) and TGF-b1 in HK-2 cells stimulated by high glucose and on calcineurin (CaN)/NFAT pathway. Whether or not the antifibrotic effect of NCTD on renal interstitium was dependent on its inhibition of CaN pathway was also investigated. Experimental concentrations of NCTD were verified by cytotoxic test and MTT assay. HK-2 cells were transfected with CaN small interference RNA (siRNA). The mRNA and protein expressions of FN, ColIV, TGF-b1, and CaN in HK-2 cells were detected by real-time PCR and western blot. The CaN/NFAT pathway was examined by indirect immunofluorescence and western blot. Our study revealed that NCTD concentrations over 5 mg/l had overt cytotoxicity on HK-2 cells. Meanwhile, both 2.5 and 5 mg/l NCTD inhibited HK-2 cell proliferation (Po0.05). NCTD inhibited the upregulation of FN, ColIV, and TGF-b1 of HK-2 cells stimulated by high glucose (Po0.05), and also significantly downregulated the expression of CaN mRNA and protein in HK-2 cells (Po0.05). In addition, not only was the nuclear translocation of NFATc inhibited, but its protein level in the nucleus was also reduced. Following CaN siRNA transfection, CaN mRNA and protein expression were significantly decreased. In contrast, the protein levels of FN, ColIV, and TGF-b1 increased in HK-2 cells stimulated by high glucose (Po0.05). However, NCTD treatment downregulated their expression. These results indicated that NCTD could decrease the expression of ECM and TGF-b1 in HK-2 cells stimulated by high glucose, downregulate CaN expression, and block the CaN/NFAT signaling pathway. However, the effect of NCTD on inhibition of the expression of ECM and TGF-b1 was not associated with its inhibition of the CaN/NFAT pathway.

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“…Central to this process is epithelial-to-mesenchymal transition (EMT) or the trans-differentiation of tubular epithelial cells into myofibroblasts [3][4][5]. Overwhelming evidence implicates TGF-β1 as the predominant cytokine mediating these phenotypical fibrotic changes [6,7]. In diabetes, production of TGF-β1 in the proximal tubule is stimulated by high glucose [8,9].…”

Section: Introductionmentioning

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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Diabetic Nephropathy: Mechanisms of Renal Disease Progression

Cited by 539 publications

References 61 publications

The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy

The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy

Norcantharidin inhibits the expression of extracellular matrix and TGF-β1 in HK-2 cells induced by high glucose independent of calcineurin signal pathway

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

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