title: Smad2 protects against TGF-β1/Smad3-mediated collagen synthesis in human hepatic stellate cells during hepatic fibrosis.
abstract: With structural similarity but functional diversity, Smad2 and Smad3 interact with each other to mediate transforming growth factor-β (TGF-β)-triggered signaling transduction. However, in the hepatic fibrosis, the detailed roles of R-Smads, and interaction between Smad2 and Smad3 are still undefined. In this setting, we established a rat model of CCl4-induced hepatic fibrosis in vivo and TGF-β1-treated hepatic stellate cell model in vitro to detect whether Smad2 and Smad3 play distinct roles in mediating liver fibrogenesis. Results indicated that both phosphorylation of Smad2 and Smad3 were detected in the hepatic stellate cells of liver fibrotic tissues and cells. Furthermore, In vitro data demonstrated that knockdown of Smad2 in human hepatic stellate cells increased expression of collagen I (Col.I), tissue inhibitor of metalloproteinase-1 (TIMP-1) whereas decreasing expression of the matrix metalloproteinases-2(MMP-2) in presence of TGF-β1 compared with control group. In contrast, knockdown of Smad3 significantly reduced TGF-β1-induced Col.I production. These findings were further evident by the results that overexpression of Smad2 attenuated the expression of Col.I and TIMP-1, but enhanced MMP-2 whereas overexpression of Smad3 showed the opposite effect. Furthermore, Smad2 suppressed the phosphorylation and nuclear translocation of Smad3, which may protect against Smad3-mediated fibrotic response. Collectively, Smad2 may be a potential therapeutic target for the treatment of hepatic fibrosis.
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Changwei
authors.initials: C
authors.lastname: Liu
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Meng
authors.forename: Cheng
authors.initials: C
authors.lastname: Huang
authors.forename: Fengyun
authors.initials: F
authors.lastname: Xu
authors.forename: Jun
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D003094:Collagen / Q000096:biosynthesis; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology; D051381:Rats; D015398:Signal Transduction; D051899:Smad2 Protein / Q000096:biosynthesis* / Q000235:genetics; D051900:Smad3 Protein / Q000096:biosynthesis* / Q000235:genetics; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; D003094:Collagen