TY - JOUR
T1 - The MicroRNA-199a/214 cluster targets E-cadherin and claudin-2 and promotes high glucose-induced peritoneal fibrosis
AU - Che, Mingwen
AU - Shi, Tiantian
AU - Feng, Shidong
AU - Li, Huan
AU - Zhang, Xiaomin
AU - Feng, Ning
AU - Lou, Weijuan
AU - Dou, Jianhua
AU - Tang, Guangbo
AU - Huang, Chen
AU - Xu, Guoshuang
AU - Qian, Qi
AU - Sun, Shiren
AU - He, Lijie
AU - Wang, Hanmin
N1 - Publisher Copyright:
Copyright © 2017 by the American Society of Nephrology.
PY - 2017/8
Y1 - 2017/8
N2 - 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.
AB - 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.
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U2 - 10.1681/ASN.2016060663
DO - 10.1681/ASN.2016060663
M3 - Article
C2 - 28428333
AN - SCOPUS:85026504204
SN - 1046-6673
VL - 28
SP - 2459
EP - 2471
JO - Journal of the American Society of Nephrology : JASN
JF - Journal of the American Society of Nephrology : JASN
IS - 8
ER -