Hepatocyte Growth Factor (HGF) Inhibits Collagen I and IV Synthesis in Hepatic Stellate Cells by miRNA-29 Induction

被引：120

作者：

Kwiecinski, Monika ^{[1
]}

Noetel, Andrea ^{[1
]}

Elfimova, Natalia ^{[1
]}

Trebicka, Jonel ^{[2
]}

Schievenbusch, Stephanie ^{[1
,3
]}

Strack, Ingo ^{[1
]}

Molnar, Levente ^{[1
]}

von Brandenstein, Melanie ^{[1
]}

Toex, Ulrich ^{[3
]}

Nischt, Roswitha ^{[4
]}

Coutelle, Oliver ^{[5
]}

Dienes, Hans Peter ^{[1
]}

Odenthal, Margarete ^{[1
]}

机构：

[1] Univ Hosp Cologne, Inst Pathol, Cologne, Germany

[2] Univ Bonn, Dept Internal Med 1, D-5300 Bonn, Germany

[3] Univ Hosp Cologne, Dept Gastroenterol & Hepatol, Cologne, Germany

[4] Univ Hosp Cologne, Dept Dermatol, Cologne, Germany

[5] Univ Hosp Cologne, Dept Internal Med, Cologne, Germany

来源：

PLOS ONE | 2011年 / 6卷 / 09期

关键词：

BETA GENE-EXPRESSION; FAT-STORING CELLS; RAT-LIVER; TRANSFORMING GROWTH-FACTOR-BETA-1; TGF-BETA; FACTOR SUPPRESSES; FIBROSIS; ACTIVATION; MICRORNAS; TRANSDIFFERENTIATION;

D O I：

10.1371/journal.pone.0024568

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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-beta (TGF-beta) 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-beta 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-beta, HGF, collagen-I and -IV mRNA, in addition to miR-29a and miR-29b were determined after HGF and TGF-beta 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-beta stimulation of HSC, in vitro. Finally, we show that during myofibroblastic transition and TGF-beta exposure the HGF-receptor, Met, is upregulated in HSC. Thus, whereas TGF-beta 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-beta take part in the anti-or profibrogenic response of HSC, respectively.

引用

页数：13

共 54 条

[31] MicroRNA-29, a Key Regulator of Collagen Expression in Systemic Sclerosis [J].