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.
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.
Department of Medicine, The University of Melbourne, Austin Health and Northern Health, VIC, Australia. johnlubel@me.com
John S
JS
Lubel
Chandana B
CB
Herath
Jorge
J
Tchongue
Josephine
J
Grace
Zhiyuan
Z
Jia
Karen
K
Spencer
David
D
Casley
Peter
P
Crowley
William
W
Sievert
Louise M
LM
Burrell
Peter W
PW
Angus
D000199:Actins / Q000378:metabolism; D000328:Adult; D000803:Angiotensin I / Q000097:blood* / Q000235:genetics / Q000627:therapeutic use; D000804:Angiotensin II / Q000097:blood; D000818:Animals; D001652:Bile Ducts / Q000473:pathology; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D005260:Female; D019698:Hepatitis C, Chronic / Q000097:blood* / Q000150:complications; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008103:Liver Cirrhosis / Q000097:blood* / Q000821:virology; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000097:blood* / Q000235:genetics / Q000627:therapeutic use; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000502:physiology*; D015854:Up-Regulation
D000199:Actins; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D000804:Angiotensin II; D000803:Angiotensin I; D012083:Renin; C118790:angiotensin I (1-7); D006909:Hydroxyproline