Oxidative stress-mediated mesangial cell proliferation requires RAC-1/reactive oxygen species production and β4 integrin expression

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

Research output: Contribution to journalArticlepeer-review

Abstract

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 β4 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 β4 integrin.

Original languageEnglish
Pages (from-to)26101-26110
Number of pages10
JournalJournal of Biological Chemistry
Volume282
Issue number36
DOIs
Publication statusPublished - Sep 7 2007

ASJC Scopus subject areas

  • Biochemistry

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