title: Sirt1 activation ameliorates renal fibrosis by inhibiting the TGF-β/Smad3 pathway.
abstract: TGF-β signaling plays an important role in the pathogenesis and progression of chronic kidney disease (CKD). Smad3, a transcription factor, is a critical fibrogenic mediator of TGF-β. Sirt1 is a NAD(+) -dependent deacetylase that has been reported to modify a number of transcription factors to exert certain beneficial health effects. This study examined the effect of Sirt1 on Smad3 and its role in CKD. Resveratrol attenuated the expression of extracelluar matrix proteins in both the remnant kidney of 5/6th nephrectomized rats and cultured mesangial cells (MMCs) exposed to TGF-β1. The effect of resveratrol was substantially attenuated in cultured MMCs for which Sirt1 had been knocked down by an shRNA lentivirus. Overexpression of Sirt1 attenuated TGF-β1-induced extracelluar matrix expression in cultured cells. Co-immunoprecipitation studies suggested that Sirt1 could bind with Smad3. Resveratrol treatment enhanced this binding and reduced acetylation levels of Smad3. Resveratrol inhibited the transcription activity of Smad3. Knockdown of Sirt1 increased acetylated Smad3 and substantially enhanced the transcriptional activity following TGF-β1. Finally, Sirt1 deficiency aggravated renal function damage and markedly enhanced fibrosis in the remnant kidney of 5/6 nephrectomized mice. Taken together, these results identify Sirt1 as an important protective factor for renal fibrosis in a CKD rodent model, and the protective function of Sirt1 is attributable to its action on TGF-β/Smad3 signaling. Therefore, we suggest that Sirt1 may be a potential therapeutic target for the treatment of CKD.
authors.affiliation: Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, 200040, China; Division of Nephrology, Affiliated Hospital of Nantong University, Nantong, 226001, China.
authors.forename: Xin-Zhong
authors.initials: XZ
authors.lastname: Huang
authors.forename: Donghai
authors.initials: D
authors.lastname: Wen
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Qionghong
authors.initials: Q
authors.lastname: Xie
authors.forename: Leting
authors.initials: L
authors.lastname: Ma
authors.forename: Yi
authors.initials: Y
authors.lastname: Guan
authors.forename: Yueheng
authors.initials: Y
authors.lastname: Ren
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Chuan-Ming
authors.initials: CM
authors.lastname: Hao
mesh_terms: D000818:Animals; D005355:Fibrosis / Q000235:genetics / Q000473:pathology; D006801:Humans; D051379:Mice; D051381:Rats; D051436:Renal Insufficiency, Chronic / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000077185:Resveratrol; D015398:Signal Transduction / Q000235:genetics; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000008:administration & dosage / Q000633:toxicity; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D051900:Smad3 Protein; C497787:Smad3 protein, rat; D013267:Stilbenes; D053773:Transforming Growth Factor beta1; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D000077185:Resveratrol
keywords: CHRONIC KIDNEY DISEASE; FIBROSIS; RESVERATROL; Sirt1