The pathophysiological role of the RAS in portal hypertension
Portal hypertension is a life-threatening complication of liver cirrhosis and is a leading cause of morbidity and mortality, resulting from variceal bleeding. Current drugs to control variceal bleeding produce sub-optimal results. Thus, there is a major need to develop and formulate therapies that could reduce the widening of portal blood vessels with a reduction in portal blood flow. Therefore, this project aims to achieve a greater understanding of portal hypertension associated with both cirrhotic as well as non-cirrhotic patients, and to develop new therapies for their treatment or prevention.
The development of portal hypertension and many of the complications of cirrhosis results from two major pathophysiological changes. The first is an increase in intrahepatic sinusoidal resistance due to both fixed obstruction of intrahepatic portal flow and active vasoconstriction of the sinusoidal bed. We have shown that the level of angiotensin II, a major vasoconstrictive peptide of the renin angiotensin system (RAS), is markedly increased in the circulation and the liver of cirrhotic patients and animal models of liver disease. We have also shown that the increased hepatic sinusoidal tone in response to angiotensin II administration was in fact greater in cirrhosis. Ang II therefore impairs hepatic perfusion and contributes to portal hypertension by increasing sinusoidal resistance. In contrast, we found that angiotensin-(1-7) peptide opposes these effects by reducing vasoconstriction in response to angiotensin II and other intrahepatic vasoconstrictors. The second and equally important contributor is increased blood flow into the mesenteric vascular bed resulting from mesenteric vasodilatation. In response to this vasodilatation, the systemic RAS is activated and angiotensin II levels are further increased in an attempt to maintain systemic blood pressure and renal perfusion. The mechanisms responsible for these complex changes are incompletely understood. To establish the role of angiotensin peptides in portal hypertension and to develop therapeutic strategies, we conduct highly original research using angiotensin peptides and their receptor blockers in cirrhotic animals administered with coloured microspheres. These treatment strategies will be expected to reduce splanchnic vasodilatation, thus improving the portal pressure in cirrhosis. In parallel, we use angiotensin peptides to directly study vascular response such as the changes in forearm blood flow in cirrhotic patients.
- Dr Chandana Herath, Senior Research Fellow
- Professor Peter Angus, Medical Director of Victorian Liver Transplant Unit
- Ms Lakmie Gunarathne, PhD student
- Professor Jonel Trebicka, Department of Internal Medicine, University of Bonn, Germany
- Dr Anthony Zulli, College of Health and Biomedicine, Victoria University
- Dr Harinda Rajapaksha, LaTrobe University
- NHMRC project grant: Novel therapies targeting the alternate renin angiotensin system in chronic liver disease (2017-2021).
- 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-peptidic 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.
- Alsaadon H, Kruzliak P, Smardencas A, Hayes A, Bader M, Angus P, Herath CB, Zulli A. Increased aortic intimal proliferation due to Mas R deletion in vitro. International Journal of Experimental Pathology 2015; 96(3):183-87.
- Herath CB, Grace JA and Angus PW. Targeting the renin angiotensin system in portal hypertension. Invited Editorial Review. World Journal of Gastrointestinal Pathophysiology 2013; 4(1): 1-11.
- Herath CB, Mak KY, Burrell LM and Angus PW. Angiotensin-(1-7) reduces the portal pressure response to angiotensin II and methoxamine via an endothelial nitric oxide mediated pathway in cirrhotic rat liver. American Journal of Physiology – Gastrointestinal and Liver Physiology 2013; 304(1):G99-108.
- Grace JA, Klein S, Herath CB, Granzow M, Schierwagen R, Masing N, Walther T, Sauerbruch T, Burrell LM, Angus PW, Trebicka J. Activation of the MAS receptor by angiotensin-(1-7) in the renin-angiotensin system mediates mesenteric vasodilatation in cirrhosis. Gastroenterology 2013; 145(4):874-84.
- 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.
- Kemp W, Kompa A, Phrommintikul A, Herath CB, Zhiyuan J, Angus P, McLean C, Roberts S, Krum H. Urotensin II modulates hepatic fibrosis and portal haemodynamic alterations in rats. American Journal of Physiology – Gastrointestinal and Liver Physiology 2009; 297(4): G762-767.
- Herath CB, Lubel JS, Jia Z, Velkoska E, Casley D, Brown L, Tikellis C, Burrell LM and Angus PW. Portal pressure responses and angiotensin peptide production in rat liver are determined by relative activity of ACE and ACE2. American Journal of Physiology – Gastrointestinal and Liver Physiology 2009; 297:G98-G106.