title: Functional implications of microRNA-215 in TGF-β1-induced phenotypic transition of mesangial cells by targeting CTNNBIP1.
abstract: Mesangial cell (MC) phenotypic transition is crucial for the progression of diabetic nephropathy. A major stimulus mediating high glucose-induced MC phenotypic transition is TGF-β1. Our current study focuses on microRNA-215 (miR-215) and investigates its role in TGF-β1-mediated MC phenotypic transition. Using real-time quantitative PCR (qRT-PCR) and northern blotting, we determined that the miR-192/215 family is dramatically upregulated under diabetic conditions both in vitro and in vivo. Gain- and loss-of-function approaches demonstrated that miR-215 inhibition significantly inhibited TGF-β1-induced mouse mesangial cell (MMC) phenotypic transition, whereas miR-215 upregulation promoted MMC phenotypic transition. Interestingly, these changes were not detected in cells that were treated with TGF-β1 and miR-192 mimics or inhibitors. These results suggest that miR-215 participates in TGF-β1-induced MMC phenotypic transition. Luciferase reporter assays were used to identify whether catenin-beta interacting protein 1 (CTNNBIP1) is a direct target of miR-215, which was predicted by bioinformatic analysis. Mechanistic studies revealed that CTNNBIP1 suppresses Wnt/β-catenin signaling and that miR-215 promotes β-catenin activation and upregulates α-SMA and fibronectin expression in TGF-β1-treated MMCs by targeting CTNNBIP1. In addition, in vivo miR-215 silencing with a specific antagomir significantly increased CTNNBIP1 protein expression, resulting in reduced β-catenin activity and decreased α-SMA and fibronectin expression in db/db mouse kidney glomeruli. Taken together, our findings indicate that miR-215 plays an essential role in MC phenotypic transition by regulating the CTNNBIP1/β-catenin pathway, which is related to the pathogenesis of diabetic nephropathy.
authors.affiliation: Institute of Nephrology of Chongqing and Department of Nephrology, Xinqiao Hospital, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Mu
authors.forename: Qi
authors.initials: Q
authors.lastname: Pang
authors.forename: Yan-Hong
authors.initials: YH
authors.lastname: Guo
authors.forename: Ji-Gang
authors.initials: JG
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Zeng
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Huang
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Bing
authors.initials: B
authors.lastname: Feng
mesh_terms: D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology; D005353:Fibronectins / Q000378:metabolism; D020868:Gene Silencing; D005920:Glomerular Mesangium / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis* / Q000378:metabolism; D012097:Repressor Proteins; D014157:Transcription Factors / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C498785:Ctnnbip1 protein, mouse; D005353:Fibronectins; C577160:MIRN215 microRNA, mouse; D035683:MicroRNAs; C539618:Mirn192 microRNA, mouse; D012097:Repressor Proteins; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D051176:beta Catenin
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