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...

Full description

Saved in:
Bibliographic Details
Published in:Journal of cellular biochemistry 2014-05, Vol.115 (5), p.996-1005
Main Authors: Huang, Xin-Zhong, Wen, Donghai, Zhang, Min, Xie, Qionghong, Ma, Leting, Guan, Yi, Ren, Yueheng, Chen, Jing, Hao, Chuan-Ming
Format: Article
Language:English
Subjects:
Acetylation
Animals
Attenuation
CHRONIC KIDNEY DISEASE
FIBROSIS
Fibrosis - genetics
Fibrosis - pathology
Humans
Immunoprecipitation
Kidney diseases
Kidneys
Mesangial cells
Mice
Pathogenesis
Rats
Renal function
Renal Insufficiency, Chronic - chemically induced
Renal Insufficiency, Chronic - drug therapy
Renal Insufficiency, Chronic - genetics
Renal Insufficiency, Chronic - pathology
RESVERATROL
Signal Transduction - genetics
Sirt1
SIRT1 protein
Sirtuin 1 - genetics
Sirtuin 1 - metabolism
Smad3 protein
Smad3 Protein - genetics
Smad3 Protein - metabolism
Stilbenes - administration & dosage
Stilbenes - toxicity
Therapeutic targets
Transcription
Transcription factors
Transforming Growth Factor beta1 - genetics
Transforming Growth Factor beta1 - metabolism
Transforming growth factor-b
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. J. Cell. Biochem. 115: 996–1005, 2014. © 2014 Wiley Periodicals, Inc.
ISSN:0730-2312
1097-4644
DOI:10.1002/jcb.24748