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.

Resveratrol attenuates type 2 diabetes mellitus by mediating mitochondrial biogenesis and lipid metabolism via Sirtuin type 1

“…Furthermore, the results of an in vivo study indicated that RSV increases SIRT1 expression and stimulates PGC-1a activity in skeletal muscle (24). The results of the present study demonstrate that RSV is able to mitigate the STZ-induced inhibition of SIRT1, PGC-1α and FOXO3a, which is in accordance with previous results (25)(26)(27). A number of previous studies have reported that INS resistance is associated with mitochondrial dysfunction (22) and these results may be caused by oxidative stress (28).…”

Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension

“…SIRT1 has been reported to deacetylate the lysine residues of a number of nuclear proteins, such as p53 (Yuan et al., 2011), NF‐κB (Salminen & Kaarniranta, 2009), PGC‐1a (Amat et al., 2009), CBP/p300 (Das, Lucia, Hansen & Tyler, 2009), and forkhead family proteins (Brunet et al., 2004). Several recent studies demonstrated that Sirt1 could inhibit TGF‐β signaling and ameliorate fibrosis (Huang et al., 2014; Kume et al., 2007; Zerr et al., 2014). In this study, we found that aging suppressed SIRT1 activity, increased TGFβ and MMP expressions, and induced fibrosis.…”

SIRT3 Blocks Aging-Associated Tissue Fibrosis in Mice by Deacetylating and Activating Glycogen Synthase Kinase 3β

“…SIRT1 has been shown to exert tissue-specific effects with regard to its ability to regulate tissue fibrosis. SIRT1 inhibits TGF-␤-mediated renal fibrosis and blocks the epithelial-to-mesenchymal transition that leads to organ fibrosis (61,62). In contrast to this, other studies report that SIRT1-deficient hearts develop reduced fibrosis following stress, while SIRT1-overexpressing hearts develop massive fibrosis with age (19,63).…”