Chao He1, Xiongying Miao, Jiequn Li, Haizhi Qi. 1. Department of General Surgery, Second Xiangya Hospital, Central South University, 139 People's Road, Changsha, 410011, Hunan, People's Republic of China.
Abstract
BACKGROUND: Both angiotensin (Ang)-II and endothelin-1 (ET-1) are involved in the pathogenesis of liver fibrosis. Activated hepatic stellate cells (HSCs) are considered a key effector of liver fibrosis. AIMS: To explore the effect of Ang-II on ET-1 expression in cultured human HSCs and the underlying mechanisms. METHODS: Human HSCs were treated with Ang-II in different concentrations (0.1, 0.5, 1, 5, or 10 nM) for different lengths of time (0.5, 1, 2, 4, or 6 h) with or without transcription inhibitor actinomycin D, Ang-II type 1 (AT1) receptor blocker losartan, AT2 receptor blocker PD123177, or different kinase inhibitors. RESULTS: Ang-II increased the ET-1 mRNA level in a statistically significant dose- and time-dependent manner within 4 h, which led to dose-dependent up-regulation of the ET-1 protein level. Actinomycin D (1 mg/ml), losartan (50 μM), and phosphatidylinositol-3 kinase inhibitor LY294002 (50 μM) abolished the promoting effect of Ang-II on ET-1 expression. Ang-II (10 nM) significantly increased the expression of α-smooth muscle actin and type I collagen in HSCs, which was abolished by losartan, LY294002, ET A receptor blocker BQ123, and ET-1 siRNA, but not PD123177 and ET B receptor blocker BQ788. CONCLUSIONS: Ang-II induces ET-1 expression in human HSCs via the AT1 receptor by the PI3 K/Akt signaling pathway. The ET-1/ET A receptor axis could mediate the promoting effects of Ang-II on HSCs' transdifferentiation into myofibroblast-like cells. This is the first evidence of crosstalk between the Ang-II/AT1 axis and the ET-1 system in regard to the pathogenesis of liver fibrosis.
BACKGROUND: Both angiotensin (Ang)-II and endothelin-1 (ET-1) are involved in the pathogenesis of liver fibrosis. Activated hepatic stellate cells (HSCs) are considered a key effector of liver fibrosis. AIMS: To explore the effect of Ang-II on ET-1 expression in cultured human HSCs and the underlying mechanisms. METHODS:Human HSCs were treated with Ang-II in different concentrations (0.1, 0.5, 1, 5, or 10 nM) for different lengths of time (0.5, 1, 2, 4, or 6 h) with or without transcription inhibitor actinomycin D, Ang-II type 1 (AT1) receptor blocker losartan, AT2 receptor blocker PD123177, or different kinase inhibitors. RESULTS: Ang-II increased the ET-1 mRNA level in a statistically significant dose- and time-dependent manner within 4 h, which led to dose-dependent up-regulation of the ET-1 protein level. Actinomycin D (1 mg/ml), losartan (50 μM), and phosphatidylinositol-3 kinase inhibitor LY294002 (50 μM) abolished the promoting effect of Ang-II on ET-1 expression. Ang-II (10 nM) significantly increased the expression of α-smooth muscle actin and type I collagen in HSCs, which was abolished by losartan, LY294002, ET A receptor blocker BQ123, and ET-1 siRNA, but not PD123177 and ET B receptor blocker BQ788. CONCLUSIONS: Ang-II induces ET-1 expression in human HSCs via the AT1 receptor by the PI3 K/Akt signaling pathway. The ET-1/ET A receptor axis could mediate the promoting effects of Ang-II on HSCs' transdifferentiation into myofibroblast-like cells. This is the first evidence of crosstalk between the Ang-II/AT1 axis and the ET-1 system in regard to the pathogenesis of liver fibrosis.
Authors: Liu Yang; Ramón Bataller; Jennyfer Dulyx; Thomas M Coffman; Pere Ginès; Richard A Rippe; David A Brenner Journal: J Hepatol Date: 2005-08 Impact factor: 25.083
Authors: Larissa Pernomian; Lilian R Gimenes; Mayara S Gomes; Bruno N do Vale; Cristina R B Cardoso; Ana M de Oliveira; Josimar D Moreira Journal: Biomed Res Int Date: 2017-09-14 Impact factor: 3.411
Authors: Jacob Richards; Amanda K Welch; Sarah J Barilovits; Sean All; Kit-Yan Cheng; Charles S Wingo; Brian D Cain; Michelle L Gumz Journal: Life Sci Date: 2014-04-08 Impact factor: 5.037