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More recently, it has been recognised that the protective RAS regulated by ACE2 counterbalances many of the deleterious effects of the classical RAS. Studies in murine models demonstrated that manipulating the protective RAS can dramatically alter many diseases including liver disease. Liver-specific overexpression of ACE2 in mice with liver fibrosis has proved to be highly effective in antagonising liver injury and fibrosis progression. Importantly, despite its highly protective role in disease pathogenesis, ACE2 is hijacked by SARS-CoV-2 as a cellular receptor to gain entry to alveolar epithelial cells, causing COVID-19, a severe respiratory disease in humans. COVID-19 is frequently life-threatening especially in elderly or people with other medical conditions. As an unprecedented number of COVID-19 patients have been affected globally, there is an urgent need to discover novel therapeutics targeting the interaction between the SARS-CoV-2 spike protein and ACE2. Understanding the role of ACE2 in physiology, pathobiology and as a cellular receptor for SARS-CoV-2 infection provides insight into potential new therapeutic strategies aiming to prevent SARS-CoV-2 infection related tissue injury. This review outlines the role of the RAS with a strong focus on ACE2-driven protective RAS in liver disease and provides therapeutic approaches to develop strategies to prevent SARS-CoV-2 infection in humans.<\/jats:p>","DOI":"10.1042\/cs20201268","type":"journal-article","created":{"date-parts":[[2020,12,9]],"date-time":"2020-12-09T05:58:07Z","timestamp":1607493487000},"page":"3137-3158","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["ACE2: from protection of liver disease to propagation of COVID-19"],"prefix":"10.1042","volume":"134","author":[{"given":"Fiona\u00a0J.","family":"Warner","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Royal Prince Alfred Hospital, Sydney, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harinda","family":"Rajapaksha","sequence":"additional","affiliation":[{"name":"School of Molecular Science, College of Science, La Trobe University, Melbourne, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas","family":"Shackel","sequence":"additional","affiliation":[{"name":"ANZAC Research Institute, Sydney, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9151-8531","authenticated-orcid":false,"given":"Chandana\u00a0B.","family":"Herath","sequence":"additional","affiliation":[{"name":"South Western Sydney Clinical School, University of New South Wales, Ingham Institute for Applied Medical Research, Sydney, Australia"},{"name":"Department of Medicine, Melbourne Medical School, University of Melbourne, Melbourne, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2020,12,7]]},"reference":[{"key":"2021113011180884700_B1","doi-asserted-by":"publisher","first-page":"1456","DOI":"10.1161\/CIRCRESAHA.120.317015","article-title":"Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2","volume":"126","author":"Gheblawi","year":"2020","journal-title":"Circ. 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