title: Angiotensin II induces endothelin-1 expression in human hepatic stellate cells.
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.
  
  
  OBJECTIVE
  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.affiliation: Department of General Surgery, Second Xiangya Hospital, Central South University, 139 People's Road, Changsha, 410011, Hunan, People's Republic of China.
authors.forename: Chao
authors.initials: C
authors.lastname: He
authors.forename: Xiongying
authors.initials: X
authors.lastname: Miao
authors.forename: Jiequn
authors.initials: J
authors.lastname: Li
authors.forename: Haizhi
authors.initials: H
authors.lastname: Qi
mesh_terms: D000803:Angiotensin I / Q000037:antagonists & inhibitors / Q000378:metabolism; D000804:Angiotensin II / Q000008:administration & dosage*; D057911:Angiotensin Receptor Antagonists / Q000008:administration & dosage; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000378:metabolism*; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology* / Q000378:metabolism; D012084:Renin-Angiotensin System
chemical_list: D057911:Angiotensin Receptor Antagonists; D019332:Endothelin-1; D000804:Angiotensin II; D000803:Angiotensin I