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J. Biol. Chem., Vol. 282, Issue 36, 26101-26110, September 7, 2007

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Oxidative Stress-mediated Mesangial Cell Proliferation Requires RAC-1/Reactive Oxygen Species Production and 4 Integrin Expression^*

Patrizia Dentelli, Arturo Rosso, Annarita Zeoli, Roberto Gambino, Luigi Pegoraro, Gianfranco Pagano, Rita Falcioni, and Maria Felice Brizzi¹

From the Department of Internal Medicine, University of Torino, Corso Dogliotti 14, 10126 Torino and the Molecular Oncogenesis Laboratory, Regina Elena Cancer Institute, Via delle Messi d'Oro, 156, 00158 Rome, Italy

Lipid abnormalities and oxidative stress, by stimulating mesangial cell (MC) proliferation, can contribute to the development of diabetes-associated renal disease. In this study we investigated the molecular events elicited by oxidized low density lipoproteins (ox-LDL) in MC. We demonstrate that in MC cultured in the presence of ox-LDL, survival and mitogenic signals on Akt and Erk1/2 MAPK pathways are induced, respectively. Moreover, as shown by the expression of the dominant negative Rac-1 construct, we first report that ox-LDL-mediated cell survival and cell cycle progression depend on Rac-1 GTPase-mediated reactive oxygen species production and on epidermal growth factor receptor transactivation. By silencing Akt and blocking Erk1/2 MAPK pathways, we also demonstrate that these signals are downstream to Rac-1/reactive oxygen species production and epidermal growth factor receptor activation. Finally, by endogenous depletion of 4 integrin, expressed in MC, we provide evidence that the expression of this adhesion molecule is essential for ox-LDL-mediated MC dysfunction. Our data identify a novel signaling pathway involved in oxidative stress-induced diabetes-associated renal disease and provide the rationale for therapeutically targeting 4 integrin.

Received for publication, April 13, 2007 , and in revised form, June 4, 2007.

^* This work was supported by grants from the Italian Association for Cancer Research (to M. F. B. and R. F.), Ministero dell'Università e Ricerca Scientifica, Cofinanziamento MURST, and Fondi ex-60% and PRIN (to M. F. B. and L. P.). 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.

¹ To whom correspondence should be addressed. Tel.: 39-011-633-5539; Fax: 39-011-663-7520; E-mail: mariafelice.brizzi{at}unito.it.

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