title: Activation of FXR protects against renal fibrosis via suppressing Smad3 expression.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China.|Department of Pathogenic Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China.
authors.forename: Jialin
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China.
authors.forename: Zhizhen
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China.
authors.forename: Haojun
authors.initials: H
authors.lastname: Xiong
authors.affiliation: Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, RI 02903, USA.
authors.forename: Rujun
authors.initials: R
authors.lastname: Gong
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China.
authors.forename: Fengtian
authors.initials: F
authors.lastname: He
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D015536:Down-Regulation; D005260:Female; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D007676:Kidney Failure, Chronic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051900:Smad3 Protein / Q000096:biosynthesis* / Q000235:genetics; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D015415:Biomarkers; D005353:Fibronectins; D018160:Receptors, Cytoplasmic and Nuclear; D051900:Smad3 Protein; D000099150:Receptor, Farnesoid X-Activated; C497790:SMAD3 protein, human