Further work needs to be conducted to validate these preliminary results. The results of this study will contribute to a better understanding of the pathophysiology of ischemic type biliary strictures and possible treatment options. KY MAK,1 R CHIN,3 J TORRESI,3 S CUNNINGHAM,4 I ALEXANDER,4 PW ANGUS,2 CB HERATH1 1Department of Medicine, The University of Melbourne, Melbourne, Australia, 2Liver Transplant Unit, Austin Health, Melbourne, Australia, 3Department of Infectious Disease, Austin Health, Melbourne, Australia, 4The Children’s Hospital at Westmead, University of Sydney, Sydney, Australia Background: Recent

selleck chemical studies suggest that the alternate arm of the RAS consisting of ACE2, angiotensin 1-7 (Ang-1-7) and its receptor, Mas, is a potential therapeutic target in liver fibrosis.1,2,3 this website ACE2 appears

to be a negative regulator of the RAS by degrading potentially deleterious vasoconstrictor and profibrotic actions angiotensin II (Ang II) to produce Ang-(1-7), a peptide that has anti-fibrotic activity. We therefore investigated a long-term therapeutic effect of ACE2 in mice with experimental liver disease. Methods: A single injection of recombinant AAV2/8 carrying murine ACE2 (rAAV2/8-ACE2) with a liver-specific promoter was intra-peritoneally administered to mice with liver disease induced by bile duct ligation (BDL), carbon tetrachloride (CCl4) injection and methionine and choline deficient (MCD) diet feeding. The mice were sacrificed 1 week (BDL) and 6 weeks (CCl4 and MCD) after ACE2 treatment. To determine hepatic fibrosis, gene and protein expressions of collagen and pro-fibrotic mediators, and effects on Ang II signaling

pathways were analyzed. Results: Untreated mice showed extensive hepatic fibrosis at 2 weeks after BDL and 8 weeks after and CCl4 Y27632 injections and MCD diet feeding. However, ACE2 therapy for 1 week (BDL) and 6 weeks (CCl4 and MCD) significantly reduced fibrosis, as reflected by marked reductions in liver hydroxyproline content and picrosirius red staining compared to controls. In both models gene expression of collagen 1 (COL1A1), alpha-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF) and transforming growth factor beta (TGF-β) were significantly down-regulated in ACE2 treated mice. These changes were accompanied by increases in hepatic levels of the antifibrotic peptide Ang-(1-7) and reduced Ang II levels, with associated reductions in membrane translocation of the cytoplasmic p67phox NADPH oxidase subunit and activation of p38 MAP kinase. Conclusion: We conclude that rAAV2/8-ACE2 reduces fibrosis by changing the intrahepatic balance of Ang II and Ang-(1-7) production in the liver and may be an effective therapeutic option for the treatment of hepatic fibrosis. 1. Grace JA., et al., Update on new aspects of the renin-angiotensin system in liver disease: clinical implications and new therapeutic options.