Review Article Role of angiotensin II in liver fibrosis-induced portal hypertension and therapeutic implications Alejandro Lugo-Baruqui, 1 José Francisco Muñoz-Valle, 2 Sigifredo Arévalo-Gallegos 3 and Juan Armendáriz-Borunda 1,4 1 Institute of Molecular Biology in Medicine, Department of Molecular Biology and Genomics, CUCS, 2 Institute of Investigation in Rheumatology and Skeletal Muscle (IIRSME), 4 OPD Civil Hospital of Guadalajara, Guadalajara, and 3 Chemistry Faculty, University of Chihuahua, Mexico Angiotensin II (AT-II) is a peptide that plays an important role in the renin-angiotensin-aldosterone (RAA) system. Tradition- ally, the RAA system has been related with states of systemic hypertension and hypoperfusion as a counterbalance mecha- nism. Recently, AT-II has been studied for its properties in the process of fibrosis in several organs, especially in the liver. AT-II is capable to stimulate the activated hepatic stellate cells, which increase expression of profibrogenic molecules like tumor growth factor-b, tissue inhibitor of metalloproteinase-1 and collagen I, among others. At the same time, AT-II is implied in the hemodynamic balance of cirrhosis and portal hypertension. Due to its profibrogenic and vasoactive properties, blockade of AT-II actions constitutes an important therapeutic target to inhibit fibrotic processes and reduction of risk of complications of portal hypertension as well. Some drugs like angiotensin-converting enzyme inhibitors or the angiotensin II receptor blockers have been studied as alternatives for the treatment of patients with cirrhosis with promising results. Nonetheless, additional research is required in order to consider these drugs as a part of the integral treatment of the patient with cirrhosis and portal hypertension. Key words: angiotensin II, rennin-angiotensin-aldosterone system, therapeutic target, portal hypertension INTRODUCTION H EPATIC CIRRHOSIS CONSTITUTES a serious problem worldwide. Hepatic failure and portal hypertension are chief complications of liver cirrhosis, which represents the end stage of a cellular damage process which involves liver fibrosis and alteration of the regular hepatic architecture and function. 1 Recently, angiotensin II (AT-II) has been implied as an important molecule in the progression of liver fibrosis. The study of the molecular mechanisms by which AT-II enhances fibrosis represents the rationale for new therapeutic strategies. 2 AT-II is an octapeptide produced by the proteolytic degradation of its precursor, angiotensin I, by the action of the angiotensin converting enzyme (ACE). Tradition- ally, AT-II has been associated with systemic hyperten- sion for its role in the renin-angiotensin-aldosterone system (RAA). Due to this hemodynamic implication, the blockade of AT-II functions might constitute a prom- ising therapeutic target for the management of patients with systemic Hypertension. 3 In the clinical setting, there are two drug classes that inhibit the effects of AT-II in the RAA system. The first group is composed by the ACE inhibitors, which impedes degradation of angiotensin I into its active form AT-II. A newer class of drugs named angiotensin II receptor blockers (ARB) has been introduced for the management of systemic hypertension as an alternative for ACE inhibitors. The action of the ARB consists in the blockade of angiotensin receptor type 1 (ATR-1). The ATR-1 is a Gq type receptor protein that activates the phospolipase C pathway. It has been shown that most of the biological actions of AT-II are mediated by acti- vation of these receptors. The over stimulation of the ATR-1 caused by pathological conditions with high levels of circulating AT-II causes a down regulation in Correspondence: Dr Juan Armendáriz-Borunda, Apdo. Postal 2-123, Guadalajara, Jal. 44281, México. Email: armdbo@gmail.com Received 21 April 2009; revision 9 June 2009; accepted 13 June 2009. Hepatology Research 2010; 40: 95–104 doi: 10.1111/j.1872-034X.2009.00581.x © 2009 The Japan Society of Hepatology 95