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Title: Activation of the Alternate Renin-Angiotensin System Correlates with the Clinical Status in Human Cirrhosis and Corrects Post Liver Transplantation.
Austin Authors: Casey, Stephen ;Schierwagen, Robert;Mak, Kai Yan;Klein, Sabine;Uschner, Frank;Jansen, Christian;Praktiknjo, Michael;Meyer, Carsten;Thomas, Daniel;Herath, Chandana B;Jones, Robert M ;Trebicka, Jonel;Angus, Peter W 
Affiliation: Victorian Liver Transplant Unit, Austin Health, Heidelberg, Victoria, Australia
Institute of Cellular Medicine, Fibrosis Research Group, Newcastle upon Tyne NE2 4HH, UK
Victorian Infectious Disease Reference Laboratory, the Peter Doherty Institute for Infection and Immunity, Melbourne Health, Melbourne 3000, Australia
Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Department of Internal Medicine I, Goethe University Clinic Frankfurt, 60323 Frankfurt, Germany
Department of Internal Medicine I, University of Bonn, 53113 Bonn, Germany.
Department of Radiology, University of Bonn, 53113 Bonn, Germany
Institute for Bioengineering of Catalonia, 08028 Barcelona, Spain
European Foundation for the Study of Chronic Liver Failure, 08021 Barcelona, Spain
Department of Gastroenterology and Hepatology, Odense University Hospital, 5000 Odense, Denmark
Issue Date: 27-Mar-2019 2019
Publication information: Journal of clinical medicine 2019; 8(4): E419
Abstract: Recent animal studies have shown that the alternate renin-angiotensin system (RAS) consisting of angiotensin-converting enzyme 2 (ACE2), angiotensin-(1⁻7) (Ang-(1⁻7)) 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' clinical status in subjects with cirrhosis. 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-(1⁻7) 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. Ang-(1⁻-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-(1⁻7) 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-(1⁻7):Ang II ratio highlighting the inter-dependence of the alternate and classical arms of the RAS and thus their potential impact on vascular tone. 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.
DOI: 10.3390/jcm8040419
ORCID: 0000-0001-7033-9956
PubMed URL: 30934723
ISSN: 2077-0383
Type: Journal Article
Subjects: cirrhosis
portal hypertension
renin-angiotensin system
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