{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T12:29:27Z","timestamp":1777552167775,"version":"3.51.4"},"reference-count":36,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","license":[{"start":{"date-parts":[[2019,10,10]],"date-time":"2019-10-10T00:00:00Z","timestamp":1570665600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hepatol Commun"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:p>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\u2010(1\u20107). In the present study, we investigated long\u2010term effects of ACE2 delivered by an adeno\u2010associated viral vector and short\u2010term effects of Ang\u2010(1\u20107) peptide in multiple drug\u2010resistant gene 2\u2010knockout (Mdr2\u2010KO) 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 (<jats:italic toggle=\"yes\">P<\/jats:italic>\u00a0&lt;\u00a00.05) and biliary fibrosis (<jats:italic toggle=\"yes\">P<\/jats:italic>\u00a0&lt;\u00a00.01) at both established (3\u20106 months of age) and advanced (7\u20109 months of age) disease compared to control vector\u2010injected Mdr2\u2010KO mice. This was accompanied by increased hepatic Ang\u2010(1\u20107) levels (<jats:italic toggle=\"yes\">P<\/jats:italic>\u00a0&lt;\u00a00.05) with concomitant reduction in hepatic Ang II levels (<jats:italic toggle=\"yes\">P<\/jats:italic>\u00a0&lt;\u00a00.05) compared to controls. Moreover, Ang\u2010(1\u20107) peptide infusion improved liver injury (<jats:italic toggle=\"yes\">P<\/jats:italic>\u00a0&lt;\u00a00.05) and biliary fibrosis (<jats:italic toggle=\"yes\">P<\/jats:italic>\u00a0&lt;\u00a00.0001) compared to saline\u2010infused disease controls. The therapeutic effects of both ACE2 therapy and Ang\u2010(1\u20107) infusion were associated with significant (<jats:italic toggle=\"yes\">P<\/jats:italic>\u00a0&lt;\u00a00.01) reduction in hepatic stellate cell (HSC) activation and collagen expression. While ACE2 therapy prevented the loss of epithelial characteristics of hepatocytes and\/or cholangiocytes <jats:italic toggle=\"yes\">in vivo<\/jats:italic>, Ang\u2010(1\u20107) prevented transdifferentiation of human cholangiocytes (H69 cells) into the collagen\u2010secreting myofibroblastic phenotype <jats:italic toggle=\"yes\">in vitro<\/jats:italic>. We showed that an increased ratio of hepatic Ang\u2010(1\u20107) to Ang II levels by ACE2 therapy results in the inhibition of HSC activation and biliary fibrosis. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> ACE2 therapy has the potential to treat patients with biliary diseases, such as PSC.<\/jats:p>","DOI":"10.1002\/hep4.1434","type":"journal-article","created":{"date-parts":[[2019,10,10]],"date-time":"2019-10-10T18:45:42Z","timestamp":1570733142000},"page":"1656-1673","source":"Crossref","is-referenced-by-count":42,"title":["Liver\u2010Targeted Angiotensin Converting Enzyme 2 Therapy Inhibits Chronic Biliary Fibrosis in Multiple Drug\u2010Resistant Gene 2\u2010Knockout Mice"],"prefix":"10.1097","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3326-3654","authenticated-orcid":false,"given":"Indu G.","family":"Rajapaksha","sequence":"first","affiliation":[{"name":"Department of Medicine,University of Melbourne,Austin Health,Heidelberg,Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lakmie S.","family":"Gunarathne","sequence":"additional","affiliation":[{"name":"Department of Medicine,University of Melbourne,Austin Health,Heidelberg,Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khashayar","family":"Asadi","sequence":"additional","affiliation":[{"name":"Anatomical Pathology,Austin Health,Heidelberg,Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sharon C.","family":"Cunningham","sequence":"additional","affiliation":[{"name":"Children's Medical Research Institute,School of Medicine,University of Sydney,Sydney,Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra","family":"Sharland","sequence":"additional","affiliation":[{"name":"Central Clinical School,School of Medicine,University of Sydney,Sydney,Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ian E.","family":"Alexander","sequence":"additional","affiliation":[{"name":"Children's Medical Research Institute,School of Medicine,University of Sydney,Sydney,Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter W.","family":"Angus","sequence":"additional","affiliation":[{"name":"Department of Medicine,University of Melbourne,Austin Health,Heidelberg,Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chandana B.","family":"Herath","sequence":"additional","affiliation":[{"name":"Department of Medicine,University of Melbourne,Austin Health,Heidelberg,Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","published-online":{"date-parts":[[2019,10,10]]},"reference":[{"key":"hep41434-bib-0001-20240114","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1016\/j.jhep.2014.02.006","article-title":"International PSC Study Group (IPSCSG). 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