NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis

J Clin Invest. 2003 Nov;112(9):1383-94. doi: 10.1172/JCI18212.


Angiotensin II (Ang II) is a pro-oxidant and fibrogenic cytokine. We investigated the role of NADPH oxidase in Ang II-induced effects in hepatic stellate cells (HSCs), a fibrogenic cell type. Human HSCs express mRNAs of key components of nonphagocytic NADPH oxidase. Ang II phosphorylated p47phox, a regulatory subunit of NADPH oxidase, and induced reactive oxygen species formation via NADPH oxidase activity. Ang II phosphorylated AKT and MAPKs and increased AP-1 DNA binding in a redox-sensitive manner. Ang II 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, Ang II 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 Ang II 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 Ang II on HSCs and plays a critical role in liver fibrogenesis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Angiotensin II / pharmacology*
  • Animals
  • Cells, Cultured
  • DNA / metabolism
  • Enzyme Activation
  • Humans
  • Lipid Peroxidation / drug effects
  • Liver / cytology*
  • Liver / drug effects
  • Liver / metabolism
  • Liver Cirrhosis, Experimental / etiology*
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinases / physiology
  • NADPH Oxidases / physiology*
  • Phosphoproteins / physiology
  • Reactive Oxygen Species
  • Signal Transduction / physiology*
  • Transcription Factor AP-1 / metabolism


  • Phosphoproteins
  • Reactive Oxygen Species
  • Transcription Factor AP-1
  • Angiotensin II
  • DNA
  • NADPH Oxidases
  • neutrophil cytosolic factor 1
  • Mitogen-Activated Protein Kinases