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2015 ; 95
(7
): 817-832
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gab.com Text
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MicroRNA-129-5p modulates epithelial-to-mesenchymal transition by targeting SIP1
and SOX4 during peritoneal dialysis
#MMPMID25961171
Xiao L
; Zhou X
; Liu F
; Hu C
; Zhu X
; Luo Y
; Wang M
; Xu X
; Yang S
; Kanwar YS
; Sun L
Lab Invest
2015[Jul]; 95
(7
): 817-832
PMID25961171
show ga
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-?1 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-?1, 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-?1. 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-?1/miR-129-5p/SIP-1 or
SOX4 pathway that has a significant role in MMT and fibrosis in the setting of
PD.