title: Upregulation of hepatic angiotensin-converting enzyme 2 (ACE2) and angiotensin-(1-7) levels in experimental biliary fibrosis.
abstract: OBJECTIVE
  Angiotensin-converting enzyme 2 (ACE2), its product, angiotensin-(1-7) and its receptor, Mas, may moderate the adverse effects of angiotensin II in liver disease. We examined the expression of these novel components of the renin angiotensin system (RAS) and the production and vasoactive effects of angiotensin-(1-7) in the bile duct ligated (BDL) rat.
  
  
  METHODS
  BDL or sham-operated rats were sacrificed at 1, 2, 3 and 4 weeks. Tissue and blood were collected for gene expression, enzyme activity and peptide measurements. In situ perfused livers were used to assess angiotensin peptide production and their effects on portal resistance.
  
  
  RESULTS
  Hepatic ACE2 gene and activity (P<0.0005), plasma angiotensin-(1-7) (P<0.0005) and Mas receptor expression (P<0.01) were increased following BDL compared to shams. Perfusion experiments confirmed that BDL livers produced increased angiotensin-(1-7) (P<0.05) from angiotensin II and this was augmented (P<0.01) by ACE inhibition. Whilst angiotensin II increased vasoconstriction in cirrhotic livers, angiotensin-(1-7) had no effect on portal resistance.
  
  
  CONCLUSIONS
  RAS activation in chronic liver injury is associated with upregulation of ACE2, Mas and hepatic conversion of angiotensin II to angiotensin-(1-7) leading to increased circulating angiotensin-(1-7). These results support the presence of an ACE2-angiotensin-(1-7)-Mas axis in liver injury which may counteract the effects of angiotensin II.
authors.affiliation: Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Vic., Australia.
authors.forename: Chandana B
authors.initials: CB
authors.lastname: Herath
authors.forename: Fiona J
authors.initials: FJ
authors.lastname: Warner
authors.forename: John S
authors.initials: JS
authors.lastname: Lubel
authors.forename: Rachael G
authors.initials: RG
authors.lastname: Dean
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Jia
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Lew
authors.forename: A Ian
authors.initials: AI
authors.lastname: Smith
authors.forename: Louise M
authors.initials: LM
authors.lastname: Burrell
authors.forename: Peter W
authors.initials: PW
authors.lastname: Angus
mesh_terms: D000803:Angiotensin I / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000085962:Angiotensin-Converting Enzyme 2; D000809:Angiotensins / Q000378:metabolism; D000818:Animals; D001652:Bile Ducts; D015870:Gene Expression; D066298:In Vitro Techniques; D008026:Ligation; D008099:Liver / Q000098:blood supply / Q000378:metabolism; D008105:Liver Cirrhosis, Biliary / Q000378:metabolism*; D008106:Liver Cirrhosis, Experimental; D008297:Male; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D011169:Portal Vein / Q000187:drug effects; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015854:Up-Regulation; D014661:Vasoconstriction
chemical_list: D000809:Angiotensins; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D044140:Receptor, Angiotensin, Type 1; D043562:Receptors, G-Protein-Coupled; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7)