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, α-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 α-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.
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Research Article|
September 14 2009
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
John S. Lubel;
*Department of Medicine, The University of Melbourne, Austin Health and Northern Health, Heidelberg, Melbourne, VIC 3081, Australia
†Austin Health, Austin Hospital, Heidelberg, Melbourne, VIC 3081, Australia
Correspondence: Dr John S. Lubel (email [email protected]).
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Chandana B. Herath;
Chandana B. Herath
*Department of Medicine, The University of Melbourne, Austin Health and Northern Health, Heidelberg, Melbourne, VIC 3081, Australia
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Jorge Tchongue;
Jorge Tchongue
‡Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Melbourne, VIC 3800, Australia
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Josephine Grace;
Josephine Grace
*Department of Medicine, The University of Melbourne, Austin Health and Northern Health, Heidelberg, Melbourne, VIC 3081, Australia
†Austin Health, Austin Hospital, Heidelberg, Melbourne, VIC 3081, Australia
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Zhiyuan Jia;
Zhiyuan Jia
*Department of Medicine, The University of Melbourne, Austin Health and Northern Health, Heidelberg, Melbourne, VIC 3081, Australia
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Karen Spencer;
Karen Spencer
*Department of Medicine, The University of Melbourne, Austin Health and Northern Health, Heidelberg, Melbourne, VIC 3081, Australia
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David Casley;
David Casley
*Department of Medicine, The University of Melbourne, Austin Health and Northern Health, Heidelberg, Melbourne, VIC 3081, Australia
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Peter Crowley;
Peter Crowley
†Austin Health, Austin Hospital, Heidelberg, Melbourne, VIC 3081, Australia
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William Sievert;
William Sievert
‡Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Melbourne, VIC 3800, Australia
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Louise M. Burrell;
Louise M. Burrell
*Department of Medicine, The University of Melbourne, Austin Health and Northern Health, Heidelberg, Melbourne, VIC 3081, Australia
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Peter W. Angus
Peter W. Angus
*Department of Medicine, The University of Melbourne, Austin Health and Northern Health, Heidelberg, Melbourne, VIC 3081, Australia
†Austin Health, Austin Hospital, Heidelberg, Melbourne, VIC 3081, Australia
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Publisher: Portland Press Ltd
Received:
December 15 2008
Revision Received:
March 16 2009
Accepted:
April 16 2009
Accepted Manuscript online:
April 16 2009
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2009 Biochemical Society
2009
Clin Sci (Lond) (2009) 117 (11): 375–386.
Article history
Received:
December 15 2008
Revision Received:
March 16 2009
Accepted:
April 16 2009
Accepted Manuscript online:
April 16 2009
Citation
John S. Lubel, Chandana B. Herath, Jorge Tchongue, Josephine Grace, Zhiyuan Jia, Karen Spencer, David Casley, Peter Crowley, William Sievert, Louise M. Burrell, Peter W. Angus; 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. Clin Sci (Lond) 1 December 2009; 117 (11): 375–386. doi: https://doi.org/10.1042/CS20080647
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