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Slit2-Robo1信号的激活促进肝纤维化

Activation of Slit2-Robo1 signaling promotes liver fibrosis

来源:Scopus 发布时间:2016-1-13
作者:Chang, J., Lan, T., Li, C., Ji, X., Zheng, L., Gou, H., Ou, Y.a, Wu, T., Qi, C., Zhang, Q., Li, J., Gu, Q., Wen, D., Cao, L., Qiao, L. , Ding, Y.b , Wang, L
机构: 广东药学院血管生物学研究
期刊: J HEPATOL 2015年12月期卷

Background & Aims The secretory protein Slit2 and its receptor Robo1 are believed to regulate cell growth and migration. Here, we aimed to determine whether Slit2-Robo1 signaling mediates the pathogenesis of liver fibrosis. Methods Serum levels of Slit2 in patients with liver fibrosis were determined by ELISA. Liver fibrosis was induced in wild-type (WT), Slit2 transgenic (Slit2-Tg) and Robo1+/-Robo2+/- double heterozygotes (Robo1/2+/-) mice by carbon tetrachloride (CCl4). The functional contributions of Slit2-Robo1 signaling in liver fibrosis and activation of hepatic stellate cells (HSCs) were investigated using primary mouse HSCs and human HSC cell line LX-2. Results Significantly increased serum Slit2 levels and hepatic expression of Slit2 and Robo1 were observed in patients with liver fibrosis. Compared to WT mice, Slit2-Tg mice were much more vulnerable to CCl4-induced liver injury and more readily develop liver fibrosis. Development of hepatic fibrosis in Slit2-Tg mice was associated with a stronger hepatic expression of collagen I and α-smooth muscle actin (α-SMA). However, liver injury and hepatic expression of collagen I and α-SMA were attenuated in CCl4-treated Robo1/2+/- mice in response to CCl4 exposure. In vitro, Robo1 neutralizing antibody R5 and Robo1 siRNA downregulated phosphorylation of Smad2, Smad3, PI3K, and AKT in HSCs independent of TGF-β1. R5 and Robo1 siRNA also inhibited the expression of α-SMA by HSCs. Finally, the protective effect of R5 on the CCl4-induced liver injury and fibrosis was further verified in mice. Conclusions Slit2-Robo1 signaling promotes liver injury and fibrosis through activation of HSCs. © 2015 European Association for the Study of the Liver.

 

通讯作者:Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou, China
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