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J. Biol. Chem., Vol. 283, Issue 35, 24061-24076, August 29, 2008

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Nox4 NAD(P)H Oxidase Mediates Src-dependent Tyrosine Phosphorylation of PDK-1 in Response to Angiotensin II

ROLE IN MESANGIAL CELL HYPERTROPHY AND FIBRONECTIN EXPRESSION^*

Karen Block, Assaad Eid, Kathy K. Griendling, Duck-Yoon Lee, Yohann Wittrant^¶, and Yves Gorin^||1

From the Departments of Medicine and ^¶Pathology and the ^||George O'Brien Kidney Research Center, University of Texas Health Science Center, San Antonio, Texas 78229-3900 and the Division of Cardiology, Emory University, Atlanta, Georgia 00000

Activation of glomerular mesangial cells (MCs) by angiotensin II (Ang II) leads to hypertrophy and extracellular matrix accumulation. Here, we demonstrate that, in MCs, Ang II induces an increase in PDK-1 (3-phosphoinositide-dependent protein kinase-1) kinase activity that required its phosphorylation on tyrosine 9 and 373/376. Introduction into the cells of PDK-1, mutated on these tyrosine residues or kinase-inactive, attenuates Ang II-induced hypertrophy and fibronectin accumulation. Ang II-mediated PDK-1 activation and tyrosine phosphorylation (total and on residues 9 and 373/376) are inhibited in cells transfected with small interfering RNA for Src, indicating that Src is upstream of PDK-1. In cells expressing oxidation-resistant Src mutant C487A, Ang II-induced hypertrophy and fibronectin expression are prevented, suggesting that the pathway is redox-sensitive. Ang II also up-regulates Nox4 protein, and siNox4 abrogates the Ang II-induced increase in intracellular reactive oxygen species (ROS) generation. Small interfering RNA for Nox4 also inhibits Ang II-induced activation of Src and PDK-1 tyrosine phosphorylation (total and on residues 9 and 373/376), demonstrating that Nox4 functions upstream of Src and PDK-1. Importantly, inhibition of Nox4, Src, or PDK-1 prevents the stimulatory effect of Ang II on fibronectin accumulation and cell hypertrophy. This work provides the first evidence that Nox4-derived ROS are responsible for Ang II-induced PDK-1 tyrosine phosphorylation and activation through stimulation of Src. Importantly, this pathway contributes to Ang II-induced MC hypertrophy and fibronectin accumulation. These data shed light on molecular processes underlying the oxidative signaling cascade engaged by Ang II and identify potential targets for intervention to prevent renal hypertrophy and fibrosis.

Received for publication, May 23, 2008

^* This work was supported, in whole or in part, by National Institutes of Health Grant K01DK-076923 (to K. B.) and the National Institutes of Health, NIDDK, George O'Brien Kidney Center (to Y. G.). This work was supported in part through an American Heart Association (National) Scientist Development Grant (to Y. G.), a grant-in-aid from the American Heart Association (South Central Affiliate) (to Y. G.), a Juvenile Diabetes Research Foundation Regular Research Grant (to Y. G.), and a National Kidney Foundation Young Investigator Award (to Y. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: Dept. of Medicine, Division of Nephrology MC 7882, University of Texas Health Science Center, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900. Tel.: 210-567-4700; Fax: 210-567-4712; E-mail: gorin{at}uthscsa.edu.

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