Attenuated hepatic inflammation and fibrosis in angiotensin type 1a receptor deficient mice

Background/Aims Pharmacological blockade of the renin–angiotensin system (RAS) attenuates liver fibrogenesis in rats. Here, we provide genetic evidence implicating angiotensin type 1 (AT1) receptors in liver fibrogenesis. Methods Wild type (WT) and AT1a knockout [AT1a (−/−)] mice were subjected to either sham operation or bile-duct ligation. Fibrosis was assessed by Sirius Red staining and hydroxyproline hepatic content. Fibrogenic and inflammatory cytokines were measured by ELISA. Results Bile duct ligation-induced elevation of serum liver enzymes was similar in WT and AT1a (−/−) mice. Bile duct ligated WT mice showed inflammatory changes and severe septal fibrosis. In contrast, AT1a (−/−) mice showed minor fibrotic lesions. Collagen accumulation was lower in AT1a (−/−) mice compared to WT mice. The increase in hepatic concentration of TGFβ1 and pro-inflammatory cytokines was attenuated in AT1a (−/−) mice compared to WT mice. Immunohistochemistry analysis revealed decreased infiltration by inflammatory cells, lipid peroxidation products as well as decreased phosphorylation of c-Jun and p42/44 MAPK in AT1a (−/−) mice compared to AT1 (+/+) mice. Conclusions AT1 receptors play an important role in the development of fibrosis. Pharmacological blockade of AT1 receptors appears to be a promising approach to treat liver fibrosis.