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Title: Angiotensin-(1-7), an alternative metabolite of the renin-angiotensin system, is up-regulated in human liver disease and has antifibrotic activity in the bile-duct-ligated rat.
Austin Authors: Lubel, John S;Herath, Chandana B;Tchongue, Jorge;Grace, Josephine A ;Jia, Zhiyuan;Spencer, Karen;Casley, David J;Crowley, Peter;Sievert, William;Burrell, Louise M ;Angus, Peter W 
Affiliation: Medicine (University of Melbourne)
Issue Date: 14-Sep-2009
Publication information: Clinical Science 2009; 117(11): 375-86
Abstract: Ang-(1-7) (angiotensin-1-7), a peptide product of the recently described ACE (angiotensin-converting enzyme) homologue ACE2, opposes the harmful actions of AngII (angiotensin II) in cardiovascular tissues, but its role in liver disease is unknown. The aim of the present study was to assess plasma levels of Ang-(1-7) in human liver disease and determine its effects in experimental liver fibrosis. Angiotensin peptide levels were measured in cirrhotic and non-cirrhotic patients with hepatitis C. The effects of Ang-(1-7) on experimental fibrosis were determined using the rat BDL (bile-duct ligation) model. Liver histology, hydroxyproline quantification and expression of fibrosis-related genes were assessed. Expression of RAS (renin-angiotensin system) components and the effects of Ang-(1-7) were examined in rat HSCs (hepatic stellate cells). In human patients with cirrhosis, both plasma Ang-(1-7) and AngII concentrations were markedly elevated (P<0.001). Non-cirrhotic patients with hepatitis C had elevated Ang-(1-7) levels compared with controls (P<0.05), but AngII concentrations were not increased. In BDL rats, Ang-(1-7) improved fibrosis stage and collagen Picrosirius Red staining, and reduced hydroxyproline content, together with decreased gene expression of collagen 1A1, alpha-SMA (smooth muscle actin), VEGF (vascular endothelial growth factor), CTGF (connective tissue growth factor), ACE and mas [the Ang-(1-7) receptor]. Cultured HSCs expressed AT1Rs (AngII type 1 receptors) and mas receptors and, when treated with Ang-(1-7) or the mas receptor agonist AVE 0991, produced less alpha-SMA and hydroxyproline, an effect reversed by the mas receptor antagonist A779. In conclusion, Ang-(1-7) is up-regulated in human liver disease and has antifibrotic actions in a rat model of cirrhosis. The ACE2/Ang-(1-7)/mas receptor axis represents a potential target for antifibrotic therapy in humans.
DOI: 10.1042/CS20080647
Journal: Clinical Science
Type: Journal Article
Subjects: Actins.metabolism
Angiotensin I.blood.genetics.therapeutic use
Angiotensin II.blood
Bile Ducts.pathology
Cells, Cultured
Drug Evaluation, Preclinical
Hepatitis C, Chronic.blood.complications
Liver Cirrhosis.blood.virology
Liver Cirrhosis, Experimental.drug therapy.etiology.pathology
Middle Aged
Peptide Fragments.blood.genetics.therapeutic use
Proto-Oncogene Proteins.metabolism
RNA, Messenger.genetics
Rats, Sprague-Dawley
Receptors, G-Protein-Coupled.metabolism
Renin-Angiotensin System.physiology
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