Abstract
SummaryEpithelial‐to‐mesenchymal transition (EMT) plays a significant role in tubulointerstitial fibrosis, which is a hallmark of diabetic nephropathy. Thus, identifying the mechanisms of EMT activation could be meaningful. In this study, loss of miR‐30c accompanied with increased EMT was observed in renal tubules of db/db mice and cultured HK2 cells exposed to high glucose. To further explore the roles of miR‐30c in EMT and tubulointerstitial fibrosis, recombinant adeno‐associated viral vector was applied to manipulate the expression of miR‐30c. In vivo study showed that overexpression of miR‐30c suppressed EMT, attenuated renal tubulointerstitial fibrosis and reduced proteinuria, serum creatinine, and BUN levels. In addition, Snail1 was identified as a direct target of miR‐30c by Ago2 co‐immunoprecipitation, luciferase reporter, and Western blot assays. Downregulating Snail1 by siRNA reduced high glucose‐induced EMT in HK2 cells, and miR‐30c mimicked the effects. Moreover, miR‐30c inhibited Snail1‐TGF‐β1 axis in tubular epithelial cells undergoing EMT and thereby impeded the release of TGF‐β1; oppositely, knockdown of miR‐30c enhanced the secretion of TGF‐β1 from epitheliums and significantly promoted proliferation of fibroblasts and fibrogenesis of myofibroblasts, aggravated tubulointerstitial fibrosis, and dysfunction of diabetic nephropathy. These results suggest a protective role of miR‐30c against diabetic nephropathy by suppressing EMT via inhibiting Snail1‐TGF‐β1 pathway.
Highlights
Diabetic nephropathy (DN) is a major complication of diabetes, and a common cause of end-stage renal disease (ESRD) worldwide
We revealed that miR-30c was a key regulator of Epithelial-to-mesenchymal transition (EMT) in DN by targeting Snail1, and over-expression of miR-30c attenuated EMT in tubular epithelial cells (TECs) as well as the profibrogenic microenvironment, and ameliorated renal tubulointerstitial fibrosis and dysfunction in DN
The results showed that miR-30c was significantly decreased in db/db mice compared with C57BL/Ks in kidney (Fig. 1A)
Summary
Diabetic nephropathy (DN) is a major complication of diabetes, and a common cause of end-stage renal disease (ESRD) worldwide. Growing evidences demonstrate that inflammation, oxidative stress, and autophagy in tubular epithelial cells (TECs) may be involved in the progression of DN, but the contribution of epithelium dedifferentiation to DN remains poorly understood(Rodriguez-Iturbe & Garcia Garcia, 2010; Navarro-Gonzalez et al, 2011; Arora & Singh, 2014; Kume & Koya, 2015). In human renal biopsies, the number of mesenchymal marker-positive TECs was associated with the increased serum creatinine level and the severity of interstitial damage (Rastaldi et al, 2002). Together, these data imply an important role of EMT in tubulointerstitial fibrosis of DN, but the mechanisms how EMT activates and contributes to tubulointerstitial fibrosis in diabetes are unclear
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