MicroRNA-129-5p modulates epithelial-to-mesenchymal transition by targeting SIP1 and SOX4 during peritoneal dialysis

Li Xiao, Xun Zhou, Fuyou Liu, Chun Hu, Xuejing Zhu, Ying Luo, Ming Wang, Xiaoxuan Xu, Shikun Yang, Yashpal S. Kanwar, Lin Sun*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Peritoneal dialysis (PD) is the most readily feasible home-dialysis method for renal replacement therapy. However, repeated use of PD can lead to induction of mesothelial/epithelial-mesenchymal transition (MMT/EMT) and fibrosis, eventually leading to ultrafiltration failure and discontinuation of PD. MicroRNA-129-5p (miR-129-5p) is believed to be a potent downstream inhibitor of TGF-β1 in renal fibrosis, but the effect of miR-129-5p on MMT/EMT relevant to PD is unknown. In this study, as determined by microRNA array analysis and confirmed by northern blot analysis and real-time PCR, we demonstrate that miRNA-129-5p is decreased in mesothelial cells isolated from effluent of patients having PD for more than 6 months extending to several years compared with those who have undergone PD for less than 6 months. The decreased expression of miR-129-5p was accompanied with alterations in EMT-related genes and the expression of respective proteins in vivo. In addition, in in vitro studies we noted that the expression of E-cadherin and claudin-1 were significantly reduced with increased cell migration in HMrSV5, a human peritoneal mesothelial cell line (HPMC), treated with TGF-β1, whereas expression of vimentin, fibronectin and transcription factors SIP1 and SOX4 increased significantly, as assessed by real-time PCR, western blot analysis and immunofluorescence microscopy. Furthermore, alteration in EMT-related genes and proteins were reversed by overexpression of miR-129-5p. No effect was observed in cells treated with miR-negative control. Meanwhile, inhibition of SIP1 and SOX4 with their respective siRNA also could decrease the expression of EMT-related genes and protein levels in HPMCs induced with TGF-β1. Finally, we demonstrate that SIP1 can inhibit the promoter activity of E-cadherin while enhancing the promoter activity of vimentin. We also observed that miR-129-5p could directly target the 3′UTR of SIP1 and SOX4 genes, and repressed their post-transcriptional activities. These data suggest that there is a novel TGF-β1/miR-129-5p/SIP-1 or SOX4 pathway that has a significant role in MMT and fibrosis in the setting of PD.

Original languageEnglish (US)
Pages (from-to)817-832
Number of pages16
JournalLaboratory Investigation
Volume95
Issue number7
DOIs
StatePublished - Jul 27 2015

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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