Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/22280
Title: Liver-Targeted Angiotensin Converting Enzyme 2 Therapy Inhibits Chronic Biliary Fibrosis in Multiple Drug-Resistant Gene 2-Knockout Mice.
Austin Authors: Rajapaksha, Indu G;Gunarathne, Lakmie S;Asadi, Khashayar ;Cunningham, Sharon C;Sharland, Alexandra;Alexander, Ian E;Angus, Peter W ;Herath, Chandana B
Affiliation: Central Clinical School School of Medicine University of Sydney Sydney Australia
Anatomical Pathology Austin Health Heidelberg Australia
Department of Medicine University of Melbourne Austin Health Heidelberg Australia
Children's Medical Research Institute School of Medicine University of Sydney Sydney Australia
Issue Date: Dec-2019
metadata.dc.date: 2019-10-31
Publication information: Hepatology communications 2019; 3(12): 1656-1673
Abstract: There is a large unmet need for effective therapies for cholestatic disorders, including primary sclerosing cholangitis (PSC), a disease that commonly results in liver failure. Angiotensin (Ang) II of the renin Ang system (RAS) is a potent profibrotic peptide, and Ang converting enzyme 2 (ACE2) of the alternate RAS breaks down Ang II to antifibrotic peptide Ang-(1-7). In the present study, we investigated long-term effects of ACE2 delivered by an adeno-associated viral vector and short-term effects of Ang-(1-7) peptide in multiple drug-resistant gene 2-knockout (Mdr2-KO) mice. These mice develop progressive biliary fibrosis with pathologic features closely resembling those observed in PSC. A single intraperitoneal injection of ACE2 therapy markedly reduced liver injury (P < 0.05) and biliary fibrosis (P < 0.01) at both established (3-6 months of age) and advanced (7-9 months of age) disease compared to control vector-injected Mdr2-KO mice. This was accompanied by increased hepatic Ang-(1-7) levels (P < 0.05) with concomitant reduction in hepatic Ang II levels (P < 0.05) compared to controls. Moreover, Ang-(1-7) peptide infusion improved liver injury (P < 0.05) and biliary fibrosis (P < 0.0001) compared to saline-infused disease controls. The therapeutic effects of both ACE2 therapy and Ang-(1-7) infusion were associated with significant (P < 0.01) reduction in hepatic stellate cell (HSC) activation and collagen expression. While ACE2 therapy prevented the loss of epithelial characteristics of hepatocytes and/or cholangiocytes in vivo, Ang-(1-7) prevented transdifferentiation of human cholangiocytes (H69 cells) into the collagen-secreting myofibroblastic phenotype in vitro. We showed that an increased ratio of hepatic Ang-(1-7) to Ang II levels by ACE2 therapy results in the inhibition of HSC activation and biliary fibrosis. Conclusion: ACE2 therapy has the potential to treat patients with biliary diseases, such as PSC.
URI: http://ahro.austin.org.au/austinjspui/handle/1/22280
DOI: 10.1002/hep4.1434
ORCID: 0000-0002-3326-3654
0000-0002-4403-7177
PubMed URL: 31832573
Type: Journal Article
Appears in Collections:Journal articles

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