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

Authors
 Ramón Bataller  ;  Robert F. Schwabe  ;  David A. Brenner  ;  John J. Lemasters  ;  Curt H. Hagedorn  ;  Robert Schoonhoven  ;  Ting Qian  ;  Jeffrey Lindquist  ;  Yong Han Paik  ;  Liu Yang  ;  Youkyung H. Choi 
Citation
 JOURNAL OF CLINICAL INVESTIGATION, Vol.112(9) : 1383-1394, 2003 
Journal Title
 JOURNAL OF CLINICAL INVESTIGATION 
ISSN
 0021-9738 
Issue Date
2003
MeSH
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
Keywords
14597764
Abstract
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 α1(I) mRNA expression, and secretion of TGF-β1 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 α-actin and expression of TGF-β1 were reduced in p47phox–/– mice. Thus, NADPH oxidase mediates the actions of Ang II on HSCs and plays a critical role in liver fibrogenesis.
Files in This Item:
T200303451.pdf Download
DOI
10.1172/JCI18212
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Paik, Yong Han(백용한)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/113568
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