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. 2021 Jan 18;11:598012. doi: 10.3389/fendo.2020.598012

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Copyright © 2021 Wang(a), Wang, Wang(b), Xiao, Guo, Tang, Zhang and Gu

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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The mechanisms of action and signaling pathways of SIRT1 in diabetic nephropathy. Diabetes mellitus (DM) can inhibit SIRT1 expression by increased expression of miR-34a-5p, miR-221, miR-9, miR-133b, miR-155-5p, and miR-199b. HIC1 can repress SIRT1 transcription in response to HG stimulation via an interaction with EZH2 and Dnmt1. Overexpression of SIRT1 can blunt CLDN1/β-catenin-Snail-mediated albuminuria in DN via the deacetylation of histones H3 and H4 with subsequent CpG methylation of Cldn1 by recruiting Dnmt1. SIRT1 activation can inhibit p66Shc expression to improve oxidative stress in DN by deacetylation of acetyl-H3. SIRT1 activation can upregulate miR-29 expression by reduction of NF-κB binding to its promotor. Overexpression of miR-29 directly targets Keap1 mRNA to decrease Keap1 expression and subsequently increase Nrf2 expression. Free Nrf2 translocates to the nucleus, where it dimerizes with members of the sMaf family and binds to ARE within regulatory regions of a wide variety of cell defense genes, including GST and NQO1. LincRNA 1700020I14Rik can interact with miR-34a-5p to inhibit cell proliferation and fibrosis in DN though the SIRT1/HIF-1α signaling pathway. LncRNA GAS5 and SOX2OT can upregulate SIRT1 expression by sponging miR-221 and miR-9, respectively. SIRT1 can inhibit TGF-β1-induced renal fibrosis and NOX4-induced oxidative stress, and stimulate PGC-1α-mediated mitochondrial biogenesis to improve DN. Finally, SIRT1 can deacetylate and activate FOXO1 to upregulate the level of autophagy, and deacetylate and inhibit p53 to inhibit apoptosis, thus improving DN. SIRT1, Sirtuin 1; DM, diabetes mellitus; miR, microRNA; HIC1, hypermethylated in cancer 1; HG, high glucose; EZH2, enhancer of zeste homolog 2; Dnmt1, DNA methyltransferase 1; CLDN1, claudin-1; DN, diabetic nephropathy; NF-κB, nuclear factor kappa B; Keap1, Kelch-like ECH-associated protein 1; Nrf2, nuclear factor erythroid 2-related factor 2; sMaf, small Maf; ARE, antioxidant response element; GST, glutathione S-transferase; NQO1, nicotinamide adenine dinucleotide phosphate (NADPH) quinone dehydrogenase 1; LincRNA, long intergenic non-coding RNA; HIF-1α, hypoxia-inducible factor-1α; LncRNA GAS5, long non-coding RNA growth arrest special 5; SOX2OT, SOX2-overlapping transcript; TGF-β1, transforming growth factor-beta 1; NOX4, NADPH oxidase 4; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator-1 alpha FOXO1, forkhead box O 1; p53, tumor protein 53.