Angiotensin-converting-enzyme 2 inhibits liver fibrosis in... : Hepatology (original) (raw)

Liver Biology/Pathobiology

Österreicher, Christoph H.1; Taura, Kojiro1; De Minicis, Samuele1; Seki, Ekihiro1; Penz-Österreicher, Melitta1; Kodama, Yuzo1; Kluwe, Johannes2; Schuster, Manfred3; Oudit, Gavin Y.4; Penninger, Josef M.5; Brenner, David A.1*†

1 University of California San Diego, School of Medicine, San Diego, CA

2 Columbia University, Department of Medicine, New York, NY

3 Apeiron Biologics, Vienna, Austria

4 University of Alberta, Division of Cardiology, Edmonton, Canada

5 Institute of Molecular Biotechnology of the Austrian Academy of Science, Vienna, Austria

* University of California San Diego, School of Medicine, Vice Chancellor Health Sciences Office, 9500 Gilman Drive #0602, La Jolla, CA 92093-0602

Email:[email protected]

Received November 25, 2008; accepted May 15, 2009.

Published online 2 August 2009 in Wiley InterScience (www.interscience.wiley.com).

Grant sponsor: Erwin Schrödinger research fellowship; Grant sponsor: Austrian Science Fund (FWF); Grant sponsor: American Liver Foundation; Grant sponsor: Fellowship-to-Faculty Transition Award; Grant sponsor: American Gastroenterology Association; Grant sponsor: National Institutes of Health (NIH); Grant sponsor: Institute of Molecular Biotechnology (IMBA); Grant sponsor: Austrian National Bank; Grant sponsor: Austrian Ministry of Science and Education; Grant sponsor: European Union (EU) network grant (EuGeneHeart).

# Potential conflict of interest: M.S. is an employee of Apeiron Biologics. M.S. and J.M.P. hold shares in Apeiron Biologics. Apeiron Biologics is a company that attempts to develop recombinant ACE2 for treatment in humans. All other authors have nothing to disclose.

† fax: 858-822-0084

Additional Supporting Information may be found in the online version of this article.

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 Ang1-7. 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 Ang1-7 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 (α-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 (CCl4) 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 Ang1-7 receptor Mas and Ang1-7 inhibited Ang II-induced phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 in cultured HSCs. Conclusion: ACE2 is a key negative regulator of the RAS and functions to limit fibrosis through the degradation of Ang II and the formation of Ang1-7. Whereas loss of ACE2 activity worsens liver fibrosis in chronic liver injury models, administration of recombinant ACE2 shows therapeutic potential. (Hepatology 2009.)