Article

Sirt1 inhibits renal tubular cell epithelial–mesenchymal transition through YY1 deacetylation in diabetic nephropathy

Authors: Lei Du1, Xuan Qian1, Yuan Li1, Xi-zhi Li1, Lin-lin He1, Liu Xu1, Yi-qi Liu1, Cheng-cheng Li1, Pu Ma1, Fang-lin Shu1, Qian Lu1, Xiao-xing Yin1
1 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
Correspondence to: Xiao-xing Yin: yinxx@xzhmu.edu.cn,
DOI: 10.1038/s41401-020-0450-2
Received: 3 December 2019
Accepted: 25 May 2020
Advance online: 17 June 2020

Abstract

Silent information regulator 1 (Sirt1) is a deacetylase, which plays an important role in the occurrence and development of diabetic nephropathy (DN). Our previous study shows that Yin yang 1 (YY1), a widely expressed zinc finger DNA/RNA-binding transcription factor, is a novel regulator of renal fibrosis in diabetic nephropathy. Since the activity of YY1 is regulated via acetylation and deacetylation modification, this study aimed to explore whether Sirt1-induced deacetylation of YY1 mediated high glucose (HG)-induced renal tubular epithelial–mesenchymal transition (EMT) and renal fibrosis in vivo and in vitro. We first confirmed that Sirt1 expression level was significantly decreased in the kidney of db/db mice and in HG-treated HK-2 cells. Diabetes-induced Sirt1 reduction enhanced the level of YY1 acetylation and renal tubular EMT. Then, we manipulated Sirt1 expression in vivo and in vitro by injecting resveratrol (50 mg·kg−1·d−1. ip) to db/db mice for 2 weeks or application of SRT1720 (2.5 μM) in HG-treated HK-2 cells, we found that activation of Sirt1 reversed the renal tubular EMT and YY1 acetylation induced by HG condition. On the contrary, Sirt1 was knocked down in db/m mice or EX527 (1 μM) was added in HK-2 cells, we found that inhibition of Sirt1 exacerbated renal fibrosis in diabetic mice and enhanced level of YY1 acetylation in HK-2 cells. Furthermore, knockdown of YY1 inhibited the ameliorating effect of resveratrol on renal tubular EMT and renal fibrosis in db/db mice. In conclusion, this study demonstrates that Sirt1 plays an important role in renal tubular EMT of DN through mediating deacetylation of YY1.
Keywords: diabetic nephropathy; Sirt1; Yin yang 1; acetylation; epithelial–mesenchymal transition; db/db mice; human proximal tubular epithelial cell line HK-2; resveratrol; SRT1720; EX527

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