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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Cell+Mol+Med
2015 ; 19
(11
): 2617-32
Nephropedia Template TP
J Cell Mol Med
2015[Nov]; 19
(11
): 2617-32
PMID26257392
show ga
Epithelial-mesenchymal transition (EMT) was reported to be involved in the
activation of hepatic stellate cells (HSCs), contributing to the development of
liver fibrosis. Epithelial-mesenchymal transition can be promoted by the Hedgehog
(Hh) pathway. Patched1 (PTCH1), a negative regulatory factor of the Hh signalling
pathway, was down-regulated during liver fibrosis and associated with its
hypermethylation status. MicroRNAs (miRNAs) are reported to play a critical role
in the control of various HSCs functions. However, miRNA-mediated epigenetic
regulations in EMT during liver fibrosis are seldom studied. In this study,
Salvianolic acid B (Sal B) suppressed the activation of HSCs in CCl4 -treated
mice and mouse primary HSCs, leading to inhibition of cell proliferation, type I
collagen and alpha-smooth muscle actin. We demonstrated that the antifibrotic
effects caused by Sal B were, at least in part, via inhibition of EMT and the Hh
pathway. In particular, up-regulation of PTCH1 was associated with decreased DNA
methylation level after Sal B treatment. Accordingly, DNA methyltransferase 1
(DNMT1) was attenuated by Sal B in vivo and in vitro. The knockdown of DNMT1 in
Sal B-treated HSCs enhanced PTCH1 expression and its demethylation level.
Interestingly, increased miR-152 in Sal B-treated cells was responsible for the
hypomethylation of PTCH1 by Sal B. As confirmed by the luciferase activity assay,
DNMT1 was a direct target of miR-152. Further studies showed that the miR-152
inhibitor reversed Sal B-mediated PTCH1 up-regulation and DNMT1 down-regulation.
Collectively, miR-152 induced by Sal B, contributed to DNMT1 down-regulation and
epigenetically regulated PTCH1, resulting in the inhibition of EMT in liver
fibrosis.