Hepatocyte Growth Factor HGF Inhibits Collagen I and IV Synthesis in Hepatic Stellate Cells by miRNA-29 InductionReportar como inadecuado




Hepatocyte Growth Factor HGF Inhibits Collagen I and IV Synthesis in Hepatic Stellate Cells by miRNA-29 Induction - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Background

In chronic liver disease, hepatic stellate cells HSC transdifferentiate into myofibroblasts, promoting extracellular matrix ECM synthesis and deposition. Stimulation of HSC by transforming growth factor-β TGF-β is a crucial event in liver fibrogenesis due to its impact on myofibroblastic transition and ECM induction. In contrast, hepatocyte growth factor HGF, exerts antifibrotic activities. Recently, miR-29 has been reported to be involved in ECM synthesis. We therefore studied the influence of HGF and TGF-β on the miR-29 collagen axis in HSC.

Methodology

HSC, isolated from rats, were characterized for HGF and Met receptor expression by Real-Time PCR and Western blotting during culture induced myofibroblastic transition. Then, the levels of TGF-β, HGF, collagen-I and -IV mRNA, in addition to miR-29a and miR-29b were determined after HGF and TGF-β stimulation of HSC or after experimental fibrosis induced by bile-duct obstruction in rats. The interaction of miR-29 with 3′-untranslated mRNA regions UTR was analyzed by reporter assays. The repressive effect of miR-29 on collagen synthesis was studied in HSC treated with miR-29-mimicks by Real-Time PCR and immunoblotting.

Principal Findings

The 3′-UTR of the collagen-1 and −4 subtypes were identified to bind miR-29. Hence, miR-29a-b overexpression in HSC resulted in a marked reduction of collagen-I and -IV synthesis. Conversely, a decrease in miR-29 levels is observed during collagen accumulation upon experimental fibrosis, in vivo, and after TGF-β stimulation of HSC, in vitro. Finally, we show that during myofibroblastic transition and TGF-β exposure the HGF-receptor, Met, is upregulated in HSC. Thus, whereas TGF-β stimulation leads to a reduction in miR-29 expression and de-repression of collagen synthesis, stimulation with HGF was definitely associated with highly elevated miR-29 levels and markedly repressed collagen-I and -IV synthesis.

Conclusions

Upregulation of miRNA-29 by HGF and downregulation by TGF-β take part in the anti- or profibrogenic response of HSC, respectively.



Autor: Monika Kwiecinski , Andrea Noetel , Natalia Elfimova , Jonel Trebicka, Stephanie Schievenbusch, Ingo Strack, Levente Molnar, Mela

Fuente: http://plos.srce.hr/



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