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.
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Acknowledgements
The work was supported by the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (No. 15KJA310005, No. 19KJA460008), the National Natural Science Foundation of China (No. 81973377), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and the Science and Technology Project of Xuzhou (No. KC18202).
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LD, QL, and XXY participated in the research design. LD, XQ, YL, CCL, XZL, LX, and YQL conducted experiments. XQ, YL, LLH, CCL, PM, and FLS performed the data analysis. LD, XQ, YL, QL, and XXY wrote or contributed to the writing of the paper.
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Du, L., Qian, X., Li, Y. et al. Sirt1 inhibits renal tubular cell epithelial–mesenchymal transition through YY1 deacetylation in diabetic nephropathy. Acta Pharmacol Sin 42, 242–251 (2021). https://doi.org/10.1038/s41401-020-0450-2
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DOI: https://doi.org/10.1038/s41401-020-0450-2
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