“Hope” for the liver? Mechanistic insight into the role of the renin-angiotensin system in hepatic fibrosis


  • Gavin E. Arteel Ph.D.

    1. Department of Pharmacology and Toxicology and the James Graham Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY
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Angiotensin II (AngII) is a pro-oxidant and fibrogenic cytokine. We investigated the role of NADPH oxidase in AngII-induced effects in hepatic stellate cells (HSCs), a fibrogenic cell type. Human HSCs express mRNAs of key components of nonphagocytic NADPH oxidase. AngII phosphorylated p47phox, a regulatory subunit of NADPH oxidase, and induced reactive oxygen species formation via NADPH oxidase activity. AngII phosphorylated AKT and MAPKs and increased AP-1 DNA binding in a redox-sensitive manner. AngII stimulated DNA synthesis, cell migration, procollagen alpha1(I) mRNA expression, and secretion of TGF-beta1 and inflammatory cytokines. These effects were attenuated by N-acetylcysteine and diphenylene iodonium, an NADPH oxidase inhibitor. Moreover, AngII induced upregulation of genes potentially involved in hepatic wound-healing response in a redox-sensitive manner, as assessed by microarray analysis. HSCs isolated from p47phox−/− mice displayed a blunted response to AngII compared with WT cells. We also assessed the role of NADPH oxidase in experimental liver fibrosis. After bile duct ligation, p47phox−/− mice showed attenuated liver injury and fibrosis compared with WT counterparts. Moreover, expression of smooth muscle alpha-actin and expression of TGF-beta1 were reduced in p47phox−/− mice. Thus, NADPH oxidase mediates the actions of AngII on HSCs and plays a critical role in liver fibrogenesis.