Activation of FXR protects against renal fibrosis via suppressing Smad3 expression.

Kai Zhao,Rujun Gong,Shan Chen,Jialin He,Zhizhen Xu,Yan Zhang,Fengtian He,Haojun Xiong,Song Li

doi:10.1038/srep37234

Abstract

Renal fibrosis is the common pathway of most chronic kidney disease progression to end-stage renal failure. The nuclear receptor FXR (farnesoid X receptor), a multiple functional transcription factor, plays an important role in protecting against fibrosis. The TGFβ-Smad signaling has a central role in kidney fibrosis. However, it remains unclear whether FXR plays direct anti-fibrotic effect in renal fibrosis via regulating TGFβ-Smad pathway. In this study, we found that the level of FXR was negatively correlated with that of Smad3 and fibronectin (a marker of fibrosis) in human fibrotic kidneys. Activation of FXR suppressed kidney fibrosis and downregulated Smad3 expression, which was markedly attenuated by FXR antagonist. Moreover, the FXR-mediated repression of fibrosis was significantly alleviated by ectopic expression of Smad3. Luciferase reporter assay revealed that FXR activation inhibited the transcriptional activity of Smad3 gene promoter. The in vivo experiments showed that FXR agonist protected against renal fibrosis and downregulated Smad3 expression in UUO mice. These results suggested that FXR may serve as an important negative regulator for manipulating Smad3 expression, and the FXR/Smad3 pathway may be a novel target for the treatment of renal fibrosis.

Highlights

Renal fibrosis is the common pathway of most chronic kidney disease (CKD) progression to end-stage renal failure[1,2,3]
We demonstrated that FXR activation suppresses kidney fibrosis by downregulating Smad[3] expression in vitro and in vivo, suggesting that FXR may serve as an important negative regulator for manipulating Smad[3] expression, and the FXR/Smad[3] pathway may be a novel target for the treatment of renal fibrosis
TGF-β1 signaling is initiated with the TGF-βreceptors oligomerization and receptor-regulated Smads (R-Smads, such as Smad[2] and Smad3) phosphorylation, which is followed by recruitment of common Smad (Co-Smad, Smad4) into a R-Smad/Co-Smad complex that translocates to the nucleus to regulate gene transcription[26,27]

Summary

Introduction

Renal fibrosis is the common pathway of most chronic kidney disease (CKD) progression to end-stage renal failure[1,2,3]. Mechanistic studies show that FXR may reduce liver cell damage and fibrosis through upregulating bile salt export pump and small heterodimer partner (SHP), thereby inhibiting the production of type I collagen[19,20]. It remains unclear whether FXR can play its anti-fibrotic effect via www.nature.com/scientificreports/. We demonstrated that FXR activation suppresses kidney fibrosis by downregulating Smad[3] expression in vitro and in vivo, suggesting that FXR may serve as an important negative regulator for manipulating Smad[3] expression, and the FXR/Smad[3] pathway may be a novel target for the treatment of renal fibrosis

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Results

Conclusion