Angiotensin II Induces Endothelin-1 Expression in Human Hepatic Stellate Cells

作者：He, Chao; Miao, Xiongying; Li, Jiequn; Qi, Haizhi^*

来源：Digestive Diseases and Sciences, 2013, 58(9): 2542-2549.

DOI：10.1007/s10620-013-2685-y

• Angiotensin II
• Endothelin-1
• Hepatic stellate cell
• Liver fibrosis
• Angiotensin II type 1 receptor
• Phosphatidylinositol-3 kinase

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 mu M), and phosphatidylinositol-3 kinase inhibitor LY294002 (50 mu M) abolished the promoting effect of Ang-II on ET-1 expression. Ang-II (10 nM) significantly increased the expression of alpha-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.

• 出版日期2013-9
• 单位中南大学