The MicroRNA-199a/214 cluster targets E-cadherin and claudin-2 and promotes high glucose-induced peritoneal fibrosis

Mingwen Che, Tiantian Shi, Shidong Feng, Huan Li, Xiaomin Zhang, Ning Feng, Weijuan Lou, Jianhua Dou, Guangbo Tang, Chen Huang, Guoshuang Xu, Qi Qian, Shiren Sun, Lijie He, Hanmin Wang

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Serum response factor (SRF) was found to be involved in the phenotypic transition and fibrosis of the peritoneal membrane during treatment with peritoneal dialysis (PD), but the exact mechanism remains unclear. SRF regulates microRNAs (miRNAs) that contain the SRF-binding consensus (CArG) element in the promoter region. Therefore,weinvestigated whether the miR-199a/214 gene cluster, which contains aCArG element in its promoter, is directly regulated by SRF. High-glucose (HG) treatment significantly unregulated the expression of the miR-199a-5p/214-3p gene cluster in human peritoneal mesothelial cells (HPMCs). By chromatin immunoprecipitation and reporter assays, we found that SRF binds to the miR-199a-5p/214-3p gene cluster promoter after HG stimulation. In vitro, in HPMCs, silencing of miR-199a-5p or miR-214-3p inhibited the HG-induced phenotypic transition and cell migration but enhanced cell adhesion, whereas ectopic expression of mimic oligonucleotides had the opposite effects. Both miR-199a-5p and miR-214-3p targeted claudin-2 and E-cadherin mRNAs. In a PD rat model, treatment with an SRF inhibitor silenced miR-199a-5p and miR-214-3p and alleviated HG-PD fluid-induced damage and fibrosis. Overall, this study reveals a novel SRF-miR-199a/miR-214-E-cadherin/claudin-2 axis that mediates damage and fibrosis in PD.

Original languageEnglish (US)
Pages (from-to)2459-2471
Number of pages13
JournalJournal of the American Society of Nephrology
Volume28
Issue number8
DOIs
StatePublished - Aug 2017

ASJC Scopus subject areas

  • Nephrology

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    Che, M., Shi, T., Feng, S., Li, H., Zhang, X., Feng, N., Lou, W., Dou, J., Tang, G., Huang, C., Xu, G., Qian, Q., Sun, S., He, L., & Wang, H. (2017). The MicroRNA-199a/214 cluster targets E-cadherin and claudin-2 and promotes high glucose-induced peritoneal fibrosis. Journal of the American Society of Nephrology, 28(8), 2459-2471. https://doi.org/10.1681/ASN.2016060663