Recent evidence indicates that the renin-angiotensin system (RAS) plays a major role in liver fibrosis. Here, we investigate whether the circulatory RAS, which is frequently activated in patients with chronic liver disease, contributes to fibrosis progression. To test this hypothesis, we increased circulatory angiotensin II (Ang II) levels in rats undergoing biliary fibrosis.
Saline or
Ang II (25 ng/kg/h) were infused into bile duct-ligated rats for 2 weeks through a subcutaneous pump. Ang II infusion increased serum levels of Ang II and augmented bile duct ligation-induced liver injury, as assessed by elevated liver serum enzymes. Moreover, it increased the hepatic concentration of inflammatory proteins (tumor necrosis factor ␣ and interleukin 1) and the infiltration of CD43-positive inflammatory cells. Ang II infusion also favored the development of vascular thrombosis and increased the procoagulant activity of tissue factor in the liver. Livers from bile duct-ligated rats infused with Ang II showed increased transforming growth factor 1 content, collagen deposition, accumulation of smooth muscle ␣-actin-positive cells, and lipid peroxidation products. Moreover, Ang II infusion stimulated phosphorylation of c-Jun and p42/44 mitogen-activated protein kinase and increased proliferation of bile duct cells. In cultured rat hepatic stellate cells (HSCs), Ang II (10 ؊8 mol/L) increased intracellular calcium and stimulated reactive oxygen species formation, cellular proliferation and secretion of proinflammatory cytokines. Moreover, Ang II stimulated the procoagulant activity of HSCs, a newly described biological function for these cells. In conclusion, increased systemic Ang II augments hepatic fibrosis and promotes inflammation, oxidative stress, and thrombogenic events. (HEPATOLOGY 2005;41: 1046-1055.)
T he renin-angiotensin system (RAS) plays an important role in diseases characterized by chronic inflammation and tissue remodeling. 1 Angiotensin II (Ang II), the main effector of the RAS, regulates key steps in the tissue remodeling process through angiotensin type 1 (AT1) receptors. 2 In target cells, Ang II induces free radical formation and oxidative stress, stimulating redox-sensitive intracellular pathways. 3 Ang II-induced biological effects include cell contraction, cell growth/ hypertrophy, and secretion of inflammatory cytokines. 4,5 Moreover, Ang II stimulates collagen deposition. 6 This latter effect is mediated by the induction of transforming growth factor 1 (TGF-1), a powerful fibrogenic cytokine. 7 Finally, Ang II induces angiogenesis and favors thrombosis development. 8,9 There is increasing evidence that Ang II may play a role in hepatic fibrosis. The systemic RAS is activated in patients with cirrhosis, and a local RAS is induced in fibrotic livers and activated hepatic stellate cells (HSCs). [10][11][12][13] The blockade of Ang II synthesis or its binding to AT1 receptors markedly ameliorates hepatic fibrosis in rats. [14][15][16][17][18][19] Moreover, patients with chronic hepatitis C and a genetic polymorphism associated with increased Ang II synthesis develop more severe hepatic fibrosis. 20 The mechanisms through which Ang II is profibrogenic in the liver are