THE RENIN-ANGIOTENSIN SYSTEM AS A TARGET TO TREAT LIVER FIBROSIS

Besides its central role in the regulation of arterial pressure, the renin-angiotensin system (RAS) is involved in tissue remodeling and fibrosis in the heart and the kidney. There is overwhelming experimental evidence that RAS also plays an important role in liver fibrogenesis. An intrahepatic RAS is expressed in chronically damaged livers and angiotensin II induces an array of fibrogenic actions in hepatic stellate cells, including increased collagen synthesis and secretion of inflammatory mediators. These effects are mediated by NADPH oxidase generated reactive oxygen species and are prevented by angiotensin type 1 receptor blockers. In addition, the more recently recognized structural homologue of ACE, ACE2, is also up-regulated during liver injury. ACE2 catalyses the conversion of AngII into Ang-(1-7) [angiotensin-(1-7)], which has anti-fibrotic, vasodilatory and anti-proliferative effects, thus counterbalancing the effects of angiotensin II in the liver. Preliminary studies in patients with chronic hepatitis C and NASH suggest that RAS blocking agents may have beneficial effects on fibrosis progression. Losartan administration reduces inflammation and down-regulates hepatic expression of fibrogenic genes. Based on this data, RAS inhibition has been proposed as an approach to treat patients with chronic liver diseases. RAS modifying agents are usually well tolerated and relatively cheap. This approach cannot be recommended in clinical practice until the results of ongoing clinical trials become available.