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

Hills, Claire E.; Squires, Paul E.

doi:10.1016/j.cytogfr.2011.06.002

Cited by 170 publications

(201 citation statements)

References 128 publications

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“…On the other hand, Yang et al (18) demonstrated that the threshold for the TGF-β1 response was reduced significantly by the complete depletion of SnoN and that a minimal amount of TGF-β1 was sufficient to trigger a full-scale TGF-β1 response under chronic disease conditions. It is widely accepted that hyperactive TGF-β1 signaling plays a crucial role in the genesis and progression of diabetic renal injuries (11,12,19). Thus, it is possible that the downregulation of SnoN protein expressino under high-glucose conditions may lead to hyperactive TGF-β1/Smad signaling and promote the pathogenesis of DN.…”

Section: Discussionmentioning

confidence: 99%

“…High glucose activates TGF-β1 signaling, which in turn stimulates tubule epithelial cells to overproduce extracellular matrix (10). A large body of evidence has indicated that TGF-β1 plays a critical role in the development of tubulointerstitial fibrosis in DN (4,[10][11][12]. However, the molecular mechanisms underlying the role of TGF-β1 in the pathogenesis of DN remain elusive.…”

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confidence: 99%

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The downregulation of SnoN expression in human renal proximal tubule epithelial cells under high-glucose conditions is mediated by an increase in Smurf2 expression through TGF-β1 signaling

Xiu-ji

Diao

Ding

et al. 2015

International Journal of Molecular Medicine

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Abstract. Transforming growth factor (TGF)-β1 is a profibrotic cytokine that plays a critical role in the progression of diabetic nephropathy (DN). Previous studies have demonstrated that the Smad transcriptional co-repressor, Ski-related novel protein N (SnoN), an antagonizer of TGF-β1/Smad signaling, is downregulated in the kidneys of diabetic rats; however, the underlying molecular mechanisms remain elusive. In the present study, we demonstrated that the upregulation of Smad ubiquitination regulatory factor-2 (Smurf2), through TGF-β1/ Smad signaling, contributes to the downregulation of SnoN under high-glucose conditions in primary human renal proximal tubule epithelial cells (hRPTECs). The hRPTECs were cultured in high-glucose (30 mmol/l D-glucose) medium in the presence or absence of either the proteasome inhibitor, MG132, or the TGF-β type I receptor kinase inhibitor, SB-431542. Small interfering RNA (siRNA) was used to silence Smurf2. The expression levels of SnoN, Smurf2, Smad2 and phosphorylated (p-)Smad2 were measured by western blot analysis and RT-qPCR. The protein levels of SnoN were markedly downregulated, while its mRNA levels were increased in the hRPTECs cultured under high-glucose conditions. The protein and mRNA levels of Smurf2 were significantly increased under high-glucose conditions. The knockdown of Smurf2 increased SnoN expression in the hRPTECs cultured in high-glucose medium. Moreover, MG132 partially inhibited SnoN degradation in the hRPTECs under high-glucose conditions and SB-431542 decreased the phosphorylation of Smad2 and the expression of Smurf2 induced under high-glucose conditions. Taken together, the findings of this study demonstrate that the downregulation of SnoN expression in hRPTECs under highglucose conditions is mediated by the increased expression of Smurf2 through the TGF-β1/Smad signaling pathway. IntroductionDiabetic nephropathy (DN) is a major microvascular complication of diabetes mellitus (DM) that invariably leads to end-stage renal disease (ESRD). Although DN was traditionally considered a primarily glomerular disease, accumulating evidence indicates that renal tubules play an important role in the pathogenesis of DN (1-3). However, the mechanisms through which the deregulation of renal tubules contributes to the development of DN remain largely unknown.Transforming growth factor (TGF)-β1 initiates intracellular signaling by binding and activating transmembrane type I and II serine/threonine kinase receptors, which in turn activate the downstream mediators, Smad2 and Smad3. Activated Smad2 and Smad3 undergo phosphorylation and heteroligomerize with Smad4 to form the Smad complex, which then translocates to the nucleus to regulate the transcription of TGF-β1 target genes (4,5). Under normal physiological conditions, TGF-β1/Smad signaling is tightly controlled by a negative regulatory mechanism. Ski-related novel protein N (SnoN) is a Smad transcriptional co-repressor (6,7) that negatively regulates TGF-β1/Smad signaling by binding and repressing Smad complexes ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The downregulation of SnoN expression in human renal proximal tubule epithelial cells under high-glucose conditions is mediated by an increase in Smurf2 expression through TGF-β1 signaling

Xiu-ji

Diao

Ding

et al. 2015

International Journal of Molecular Medicine

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“…As summarised in a recent review, TGF-β1 binds to a trans-membrane TGF-β receptor II (TBRII) and initiates several intracellular signalling cascades, including small mothers against decapentaplegic (SMAD) and mitogen-activated protein kinases such as extracellular regulated kinase, p38 and Jun kinase [42]. SMADs are subdivided into three classes: (1) receptor regulated SMADs (SMAD1, -2, -3, -5 and −8); (2) the common SMADs (SMAD4); and (3) the inhibitory SMADs (SMAD6 and −7) [43].…”

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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“…TGF-β signaling is critical in promoting liver fibrosis (15,16). While, according to the results of the present study, inhibition by S17902 and POP overexpression did not affect TGF-β1 expression and p-Smad2/3 levels in HSC-T6 cells, POP participated in the regulation of Smad7 levels.…”

Section: Discussionmentioning

confidence: 57%

“…Among these Prolyl oligopeptidase attenuates hepatic stellate cell activation through induction of Smad7 and PPAR-γ growth factors, TGF-β1 is recognized as a major profibrogenic cytokine by promoting and maintaining HSC activation, proliferation, as well as collagen production and deposition through the TGF-β/Smad pathway (15)(16)(17)(18). Peroxisome proliferator activated receptor-γ (PPAR-γ) was initially identified as a key regulator of adipogenesis (19), while increasing evidence has confirmed that PPAR-γ is a key factor in HSC activation and phenotypic alteration, maintaining HSCs in a quiescent phase, and suppressing the production of type I collagen, α-SMA and TGF-β1.…”

Section: Introductionmentioning

confidence: 99%

Prolyl oligopeptidase attenuates hepatic stellate cell activation through induction of Smad7 and PPAR-γ

Zhou

Wang

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Prolyl oligopeptidase (POP) is a serine endopeptidase widely distributed in vivo with high activity in the liver. However, its biological functions in the liver have remained largely elusive. A previous study by our group has shown that POP produced N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) and thereby exerted an anti-fibrogenic effect on hepatic stellate cells (HSCs) in vitro. It was therefore hypothesized that POP may affect the activation state of HSCs and has an important role in liver fibrosis. The HSC-T6 immortalized rat liver stellate cell line was treated with the POP inhibitor S17092 or transfected with recombinant lentivirus to overexpress POP. Cell proliferation and apoptosis were determined using a Cell Counting Kit-8 and flow cytometry, respectively. The activation status of HSCs was determined by examination of the expression of α-smooth muscle actin (α-SMA), collagen I, monocyte chemoattractant protein-1 (MCP-1), transforming growth factor (TGF)-β-Smad signaling and peroxisome proliferator activated receptor-γ (PPAR-γ). Inhibition by S17092 decreased, whereas lentiviral expression increased the activity of POP and cell proliferation, while neither of the treatments affected cell apoptosis. Of note, S17092 significantly increased, whereas POP overexpression decreased the expression of α-SMA and MCP-1 without affecting the expression of collagen I and TGF-β1. Furthermore, S17092 caused a reduction, whereas POP overexpression caused an upregulation of Smad7 protein and PPAR-γ, but not phosphorylated-Smad2/3 expression. In conclusion, POP attenuated the activation of HSCs through inhibition of TGF-β signaling and induction of PPAR-γ, which may have therapeutic potential in liver fibrosis.

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

Cited by 170 publications

References 128 publications

The downregulation of SnoN expression in human renal proximal tubule epithelial cells under high-glucose conditions is mediated by an increase in Smurf2 expression through TGF-β1 signaling

The downregulation of SnoN expression in human renal proximal tubule epithelial cells under high-glucose conditions is mediated by an increase in Smurf2 expression through TGF-β1 signaling

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

Prolyl oligopeptidase attenuates hepatic stellate cell activation through induction of Smad7 and PPAR-γ

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