Angiotensin II (Ang II) stimulates hypertrophy of glomerular mesangial cells. The signalling mechanism by which Ang II exerts this effect is not precisely known. Downstream potential targets of Ang II are the extracellular-signal-regulated kinases 1 and 2 (ERK1/ERK2). We demonstrate that Ang II activates ERK1/ERK2 via the AT1 receptor. Arachidonic acid (AA) mimics the action of Ang II on ERK1/ERK2 and phospholipase A2 inhibitors blocked Ang II-induced ERK1/ERK2 activation. The antioxidant N-acetylcysteine as well as the NAD(P)H oxidase inhibitors diphenylene iodonium and phenylarsine oxide abolished both Ang II- and AA-induced ERK1/ERK2 activation. Moreover, dominant-negative Rac1 (N17Rac1) blocks activation of ERK1/ERK2 in response to Ang II and AA, whereas constitutively active Rac1 resulted in an increase in ERK1/ERK2 activity. Antisense oligonucleotides for Nox4 NAD(P)H oxidase significantly reduce activation of ERK1/ERK2 by Ang II and AA. We also show that protein synthesis in response to Ang II and AA is inhibited by N17Rac1 or MEK (mitogen-activated protein kinase/ERK kinase) inhibitor. These results demonstrate that Ang II stimulates ERK1/ERK2 by AA and Nox4-derived reactive oxygen species, suggesting that these molecules act as downstream signal transducers of Ang II in the signalling pathway linking the Ang II receptor AT1 to ERK1/ERK2 activation. This pathway involving AA, Rac1, Nox4, reactive oxygen species and ERK1/ERK2 may play an important role in Ang II-induced mesangial cell hypertrophy.
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Research Article|
June 22 2004
Angiotensin II-induced ERK1/ERK2 activation and protein synthesis are redox-dependent in glomerular mesangial cells
Yves GORIN;
Yves GORIN
1
*Department of Medicine, The University of Texas Health Science Center, San Antonio, TX 78229-3900, U.S.A.
1To whom correspondence should be addressed, at Division of Nephrology, Department of Medicine, The University of Texas Health Science Center, MC 7882, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, U.S.A. (e-mail [email protected]).
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Jill M. RICONO;
Jill M. RICONO
*Department of Medicine, The University of Texas Health Science Center, San Antonio, TX 78229-3900, U.S.A.
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Brent WAGNER;
Brent WAGNER
*Department of Medicine, The University of Texas Health Science Center, San Antonio, TX 78229-3900, U.S.A.
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Nam-Ho KIM;
Nam-Ho KIM
*Department of Medicine, The University of Texas Health Science Center, San Antonio, TX 78229-3900, U.S.A.
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Basant BHANDARI;
Basant BHANDARI
*Department of Medicine, The University of Texas Health Science Center, San Antonio, TX 78229-3900, U.S.A.
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Goutam Ghosh CHOUDHURY;
Goutam Ghosh CHOUDHURY
*Department of Medicine, The University of Texas Health Science Center, San Antonio, TX 78229-3900, U.S.A.
†Geriatric Research, Education, and Clinical Center, San Antonio, TX, U.S.A.
‡South Texas Veterans Health Care System, Audie L. Murphy Memorial Hospital Division, San Antonio, TX, U.S.A.
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Hanna E. ABBOUD
Hanna E. ABBOUD
*Department of Medicine, The University of Texas Health Science Center, San Antonio, TX 78229-3900, U.S.A.
‡South Texas Veterans Health Care System, Audie L. Murphy Memorial Hospital Division, San Antonio, TX, U.S.A.
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Publisher: Portland Press Ltd
Received:
October 22 2003
Revision Received:
March 02 2004
Accepted:
March 18 2004
Accepted Manuscript online:
March 18 2004
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2004
Biochem J (2004) 381 (1): 231–239.
Article history
Received:
October 22 2003
Revision Received:
March 02 2004
Accepted:
March 18 2004
Accepted Manuscript online:
March 18 2004
Citation
Yves GORIN, Jill M. RICONO, Brent WAGNER, Nam-Ho KIM, Basant BHANDARI, Goutam Ghosh CHOUDHURY, Hanna E. ABBOUD; Angiotensin II-induced ERK1/ERK2 activation and protein synthesis are redox-dependent in glomerular mesangial cells. Biochem J 1 July 2004; 381 (1): 231–239. doi: https://doi.org/10.1042/BJ20031614
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