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This Article Full Text Full Text (PDF) All Versions of this Article: 293/6/F1889    most recent 00112.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Ding, G. Articles by Yang, T. Search for Related Content PubMed PubMed Citation Articles by Ding, G. Articles by Yang, T.

ANG II induces c-Jun NH₂-terminal kinase activation and proliferation of human mesangial cells via redox-sensitive transactivation of the EGFR

¹Department of Pediatrics, Second Affiliated Hospital, ²Center of Pediatric Nephrology, ³Department of Nephrology, and ⁴Department of Neurology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; and ⁵Division of Nephrology, University of Utah and Salt Lake Veterans Affairs Medical Center, Salt Lake City, Utah

Submitted 5 March 2007 ; accepted in final form 27 August 2007

We previously showed that ANG II induces mesangial cell (MC) proliferation via the JNK-activator protein-1 pathway. The present study attempted to determine the upstream mediators of JNK activation, with emphasis on reactive oxygen species (ROS) and the epidermal growth factor (EGF) receptor (EGFR). In cultured human MCs (HMCs), as early as 3 min, ANG II time dependently increased intracellular ROS production, which was sensitive to 10 µM diphenyleneiodonium sulfate and 500 µM apocynin, two structurally distinct NADPH oxidase inhibitors. In contrast, inhibitors of other oxidant-producing enzymes, including the mitochondrial complex I inhibitor rotenone, the xanthine oxidase inhibitor allopurinol, the cyclooxygenase inhibitor indomethacin, the lipoxygenase inhibitor nordihydroguiaretic acid, the cytochrome P-450 oxygenase inhibitor ketoconazole, and the nitric oxide synthase inhibitor N^G-nitro-L-arginine methyl ester, were without effect. ANG II-induced ROS generation was inhibited by the angiotensin type 1 receptor antagonist losartan (10 µM) but not the angiotensin type 2 receptor antagonist PD-123319 (10 µM). ANG II induced translocation of p47^phox and p67^phox from the cytosol to the membrane. The antioxidants almost abolished the ANG II mitogenic response, as assessed by [³H]thymidine incorporation and cell number, associated with a remarkable blockade of the activation of EGFR (90% inhibition) and JNK (83% inhibition). The EGFR inhibitor AG-1478 was able to mimic the effect of antioxidants, in that it inhibited the mitogenic response and the JNK activation following ANG II treatment. Together, these data suggest that the ROS-EGFR-JNK pathway is involved in transducing the proliferative effect of ANG II in cultured HMCs.

glomerular disease; reactive oxygen species; cell growth

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