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

Background/Aims: Pharmacological blockade of the renin-angiolensin 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 ATla knockout [AT1a (-/-)] nice were subjected to either sham operation or bileduct ligation. Fibrosis was assessed by Sirius Red staining a id hydroxyproline hepatic content. Fibrogenic and inflammatory cytokines were measured by ELISA. Results: Bile duct ligation-induced elevation of serum liver enymes was similar in WT and ATla (-/-) mice. Bile duct ligated WT mice showed inflammatory changes and severe septal fibrosis. In contrast, ATla (-/-) mice showed minor fibrotic lesions. Collagen accumulation was lower in AT hi (-/-) mice compared to WT mice. The increase in hepatic concentration of TGF beta 1 and pro-inflammatory cytokines was attenuated in ATla (-/-) 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 ATla (-/-) 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. (c) 2005 European Association for the Study of the Liver. Publiislted by Elsevier B.V. All rights reserved.