{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T12:11:29Z","timestamp":1786968689997,"version":"build-2736575974"},"reference-count":35,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2019,3,27]],"date-time":"2019-03-27T00:00:00Z","timestamp":1553644800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Health and Medical Research Council (NHMRC) of Australia","award":["1062372"],"award-info":[{"award-number":["1062372"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Introduction: Recent animal studies have shown that the alternate renin-angiotensin system (RAS) consisting of angiotensin-converting enzyme 2 (ACE2), angiotensin-(1\u20137) (Ang-(1\u20137)) and the Mas receptor is upregulated in cirrhosis and contributes to splanchnic vasodilatation and portal hypertension. To determine the potential relevance of these findings to human liver disease, we evaluated its expression and relationship to the patients\u2019 clinical status in subjects with cirrhosis. Methods: Blood sampling from peripheral and central vascular beds was performed intra-operatively for cirrhotic patients at the time of liver transplantation (LT) or trans-jugular intra-hepatic portosystemic shunt (TIPS) procedures to measure angiotensin II (Ang II) and Ang-(1\u20137) peptide levels and ACE and ACE2 enzyme activity. Relevant clinical and hemodynamic data were recorded pre-operatively for all subjects and peripheral blood sampling was repeated 3 months or later post-operatively. Results: Ang-(1\u2013-7) and ACE2 activity were up-regulated more than twofold in cirrhotic subjects both at the time of LT and TIPS and levels returned to comparable levels as control subjects post-transplantation. Ang-(1\u20137) levels correlated positively with the degree of liver disease severity, as measured by the model for an end-stage liver disease (MELD) and also with clinical parameters of pathological vasodilatation including cardiac output (CO). There were strong correlations found between the ACE2:ACE and the Ang-(1\u20137):Ang II ratio highlighting the inter-dependence of the alternate and classical arms of the RAS and thus their potential impact on vascular tone. Conclusions: In human cirrhosis, the alternate RAS is markedly upregulated and the activation of this system is associated strongly with features of the hyperdynamic circulation in advanced human cirrhosis.<\/jats:p>","DOI":"10.3390\/jcm8040419","type":"journal-article","created":{"date-parts":[[2019,3,29]],"date-time":"2019-03-29T03:38:52Z","timestamp":1553830732000},"page":"419","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Activation of the Alternate Renin-Angiotensin System Correlates with the Clinical Status in Human Cirrhosis and Corrects Post Liver Transplantation"],"prefix":"10.3390","volume":"8","author":[{"given":"Stephen","family":"Casey","sequence":"first","affiliation":[{"name":"Liver Unit, Austin Health, Melbourne 3084, Australia"},{"name":"Department of Medicine, Austin Health, University of Melbourne, Melbourne 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Schierwagen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University of Bonn, 53113 Bonn, Germany"},{"name":"Department of Internal Medicine I, Goethe University Clinic Frankfurt, 60323 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai Yan","family":"Mak","sequence":"additional","affiliation":[{"name":"Department of Medicine, Austin Health, University of Melbourne, Melbourne 3084, Australia"},{"name":"Victorian Infectious Disease Reference Laboratory, the Peter Doherty Institute for Infection and Immunity, Melbourne Health, Melbourne 3000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Klein","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University of Bonn, 53113 Bonn, Germany"},{"name":"Department of Internal Medicine I, Goethe University Clinic Frankfurt, 60323 Frankfurt, Germany"},{"name":"Institute of Cellular Medicine, Fibrosis Research Group, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Uschner","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University of Bonn, 53113 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Jansen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University of Bonn, 53113 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7033-9956","authenticated-orcid":false,"given":"Michael","family":"Praktiknjo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University of Bonn, 53113 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten","family":"Meyer","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Bonn, 53113 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Thomas","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Bonn, 53113 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandana","family":"Herath","sequence":"additional","affiliation":[{"name":"Department of Medicine, Austin Health, University of Melbourne, Melbourne 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Jones","sequence":"additional","affiliation":[{"name":"Liver Unit, Austin Health, Melbourne 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7028-3881","authenticated-orcid":false,"given":"Jonel","family":"Trebicka","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University of Bonn, 53113 Bonn, Germany"},{"name":"Department of Internal Medicine I, Goethe University Clinic Frankfurt, 60323 Frankfurt, Germany"},{"name":"Institute for Bioengineering of Catalonia, 08028 Barcelona, Spain"},{"name":"European Foundation for the Study of Chronic Liver Failure, 08021 Barcelona, Spain"},{"name":"Department of Gastroenterology and Hepatology, Odense University Hospital, 5000 Odense, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Angus","sequence":"additional","affiliation":[{"name":"Liver Unit, Austin Health, Melbourne 3084, Australia"},{"name":"Department of Medicine, Austin Health, University of Melbourne, Melbourne 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,3,27]]},"reference":[{"key":"ref_1","first-page":"199","article-title":"Endothelial dysfunction in the regulation of cirrhosis and portal hypertension","volume":"32","author":"Iwakiri","year":"2012","journal-title":"Liver Int. 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