Role of angiotensin and NADPH oxidase in liver fibrosis

Fibrosis is characterized by formation of scarring tissue, leading to the conversion of normal liver architecture into structurally abnormal nodules, which lack normal function. It may develop as the consequence of chronic liver diseases of any origin. To date, therapies are not available to treat fibrosis. Understanding the pathophysiology will lead to novel strategies to treat liver fibrosis. A growing body of evidence indicates that analogous to other organs the renin-angiotensin-system (RAS) is also involved in liver fibrogenesis. The RAS is systemically activated in patients with cirrhosis accompanied by elevated serum angiotensin (Ang) I and II levels. A local RAS is expressed in chronically damaged livers, and activated hepatic stellate cells (HSCs), the major collagen producing cell in the liver, express all components of the RAS and synthesize Ang II. Ang II exerts powerful fibrogenic, inflammatory and oxidative effects, and the inhibition of Ang II markedly attenuate liver fibrosis in experimental models. The major mediator of the effects of Ang II is the activation of NADPH oxidase including changes in gene expression induced by Ang II. To further characterize and clarify the role of the RAS in liver fibrogenesis, knockout and knockin mice in two complimentary models of hepatic fibrosis are studied. It will be assessed how Ang II modulates programmed cell death of activated HSCs which may represent a critical pathway of resolution of hepatic fibrosis in vivo. To date, only Ang II has been demonstrated to activate NADPH oxidase in HSCs. Four critical agonists in hepatic fibrosis, PDGF, TGF-beta1, TNF-alpha, and leptin will be assessed for the ability to induce NADPH oxidase. A microarray approach will be used to investigate the pattern of gene expression mediated by NADPH oxidase induced by these four agonists.