Therapies targeting the renin angiotensin system (RAS) in liver fibrosis
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Liver cirrhosis and its sequelae of liver failure, is now one of the world’s leading causes of chronic illness and death. As a result, there is a major need to develop antifibrotic therapies which can prevent liver scarring and the development of cirrhosis in patients with chronic liver disease. The broad aim of this project is to achieve a greater understanding of chronic liver disease such as cirrhosis and to develop new therapies for their treatment or prevention.
The classical view of the RAS is of a linear cascade in which angiotensin converting enzyme (ACE) is a key enzyme, converting angiotensin I (Ang I) to the potent vasoconstrictor and profibrotic cytokine Ang II, which acts via the angiotensin II type 1 receptor (AT1R). It is now known that there is alternate arm of the RAS in which ACE2, a homolog of ACE, degrades Ang II and generates angiotensin-(1-7) (Ang-(1-7)), which in contrast to Ang II, has vasodilatory, anti-growth and anti-proliferative actions. In most tissues these effects are mediated in part by the Mas receptor, a G-protein-coupled receptor (GPCR). This ACE2-angiotensin-(1-7)-Mas receptor axis is thought to intrinsically regulate the RAS system by reducing Ang II levels and producing Ang-(1-7), thus counterbalancing the potentially harmful effects of Ang II. ACE2 therefore plays a key role in counterbalancing the RAS system in pathological states such as cirrhosis. Thus, we use an experimental gene therapy approach to ameliorate liver fibrosis in murine models as well as in a humanized murine model of liver disease. The humanized mice are a perfect model for testing the drugs before the commencement of clinical trials in human patients.
- Dr Chandana Herath, Senior Research Fellow
- Professor Peter Angus, Medical Director of Victorian Liver Transplant Unit
- Dr Kai Yen Mak, Research Officer
- Ms Ping Huang, Research Assistant
- Ms Indu Rajapaksha, PhD student
- Prof Ian Alexander, Childrens Hospital Westmead, University of Sydney
- A/Prof Sof Andrikopoulos, Department of Medicine, Austin Health, The University of Melbourne
- A/Prof Alexandra Sharland, Department of Surgery, Central Clinical School, University of Sydney
- NHMRC project grant: Novel therapies targeting the alternate renin angiotensin system in chronic liver disease (2017-2021).
- Mak KY, Rajapaksha IG, Angus PW, Herath CB. The adeno-associated virus - A safe and effective vehicle for liver-specific gene therapy of inherited and non-inherited diseases. Current Gene Therapy. Mar 14, 2017 [Epub ahead of print].
- Klein S, Herath CB, Schierwagen R, Grace JA, Haltenhoj T, Uschner FE, Strassburg CP, Sauerbruch T, Walther T, Angus PW, , Trebicka J. Hemodynamic effects of the non-pptidic angiotensin-(1-7) agonist AVE0991 in liver cirrhosis. PLOS ONE. 2015 Sep 25;10(9):e0138732.
- Mak KY, Chin R, Cunningham S, Habib MR, Toressi J, Sharland AF, Alexander IE, Angus PW, Herath CB. ACE2 gene therapy using adeno-associated viral vector inhibits liver fibrosis in mice. Molecular Therapy 2015; 23(9): 1434-43.
- Herath CB, Mak K, Angus PW. Role of the alternate RAS in liver disease and the GI tract. In 'The protective arm of the renin angiotensin system' (Eds, Unger T, Santos R), ELSEVIER Publishers Inc. Chapter 34, 2015.
- Yeung LW, Guruge KS, Taniyasu S, Yamashita N, Angus PW, Herath CB. Profiles of perfluoroalkyl substances in the liver and serum of patients with liver cancer and cirrhosis in Australia. Ecotoxicology and Environment Safety. 2013; 96:139-46.
- Garg M, Angus PW, Burrell LM, Herath CB, Gibson PR and Lubel JS. The pathophysiological roles of the renin–angiotensin system in the gastrointestinal tract. Review. Alimentary Pharmacology and Therapeutics 2012; 35(4):414-28.
- Grace JA, Herath CB, Mak KY, Burrell LM and Angus PW. Update on new aspects of the renin-angiotensin system in liver disease: clinical implications and new therapeutic options. Review. Clinical Science (London) 2012; 123(4):225-39.
- Neo JH, Ager EI, Angus PW, Zhu J, Herath CB, Christophi C. Changes in the renin angiotensin system during the development of colorectal cancer liver metastases. BMC Cancer 2010; Apr 10 [Epub ahead of print].
- Herath CB, Warner FJ, Lubel JS, Dean RG, Jia Z, Lew RA, Smith AI, Burrell LM, Angus PW. Upregulation of hepatic angiotensin-converting enzyme 2 (ACE2) and angiotensin-(1-7) levels in experimental biliary fibrosis. Journal of Hepatology 2007; 47:387-95.
- Paizis G, Tikellis C, Cooper ME, Schembri JM, Lew RA, Smith AI, Shaw T, Warner FJ, Zuilli A, Burrell LM, Angus PW. Chronic liver injury in rats and humans upregulates the novel enzyme angiotensin converting enzyme 2. Gut 2005 54:1790-6.