title: Angiotensin-converting-enzyme 2 inhibits liver fibrosis in mice.
abstract: The renin-angiotensin system (RAS) plays a major role in liver fibrosis. Recently, a homolog of angiotensin-converting-enzyme 1 (ACE1), termed ACE2, has been identified that appears to be a negative regulator of the RAS by degrading Ang II to Ang(1-7). The aim of this study was to characterize the long-term effects of gene deletion of ACE2 in the liver, to define the role of ACE2 in acute and chronic liver disease, and to characterize the role of Ang(1-7) in hepatic stellate cell (HSC) activation. Ace2 knockout (KO) mice and wild-type (wt) littermates underwent different models of acute and chronic liver injury. Liver pathology was analyzed by histology, immunohistochemistry, alpha smooth muscle actin (alpha-SMA) immunoblotting, and quantitative polymerase chain reaction (qPCR). Murine HSCs were isolated by collagenase-pronase-perfusion, and density gradient centrifugation. One-year-old ace2 KO mice spontaneously developed an inflammatory cell infiltration and mild hepatic fibrosis that was prevented by treatment with irbesartan. Ace2 KO mice showed increased liver fibrosis following bile duct ligation for 21 days or chronic carbon tetrachloride (CCl(4)) treatment. In contrast, ace2 KO mice subjected to acute liver injury models did not differ from wt littermates. Treatment with recombinant ACE2 attenuated experimental fibrosis in the course of cholestatic and toxic liver injury. HSCs express the Ang(1-7) receptor Mas and Ang(1-7) inhibited Ang II-induced phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 in cultured HSCs.
  
  
  CONCLUSIONS
  ACE2 is a key negative regulator of the RAS and functions to limit fibrosis through the degradation of Ang II and the formation of Ang(1-7). Whereas loss of ACE2 activity worsens liver fibrosis in chronic liver injury models, administration of recombinant ACE2 shows therapeutic potential.
authors: University of California San Diego, School of Medicine, San Diego, CA 92093-0602, USA.
authors: Christoph H
authors: CH
authors: Osterreicher
authors: Kojiro
authors: K
authors: Taura
authors: Samuele
authors: S
authors: De Minicis
authors: Ekihiro
authors: E
authors: Seki
authors: Melitta
authors: M
authors: Penz-Osterreicher
authors: Yuzo
authors: Y
authors: Kodama
authors: Johannes
authors: J
authors: Kluwe
authors: Manfred
authors: M
authors: Schuster
authors: Gavin Y
authors: GY
authors: Oudit
authors: Josef M
authors: JM
authors: Penninger
authors: David A
authors: DA
authors: Brenner
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology; D000804:Angiotensin II / Q000378:metabolism; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D002252:Carbon Tetrachloride Poisoning / Q000517:prevention & control; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017353:Gene Deletion; D055166:Hepatic Stellate Cells / Q000187:drug effects; D008026:Ligation; D008103:Liver Cirrhosis / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012084:Renin-Angiotensin System / Q000502:physiology
chemical_list: D010446:Peptide Fragments; D011994:Recombinant Proteins; D000804:Angiotensin II; D000803:Angiotensin I; D048049:Extracellular Signal-Regulated MAP Kinases; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7)