Lipid abnormalities and oxidative stress, by stimulating mesangial cell (MC) proliferation can contribute to the development of diabetes-associated renal disease. In the present 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 (ROS) production and on epidermal growth factor receptor (EGFR) transactivation. By silencing Akt and blocking Erk1/2 MAPK pathways we also demonstrate that these signals are downstream to Rac-1/ROS production and EGFR activation. Finally, by endogenous depletion of 4 integrin, expressed in MC, we provide evidences that the expression of this adhesion molecule is essential for ox-LDL-mediated MC dysfunction. Our data identify a novel signalling pathway involved in oxidative stress-induced diabetes-associated renal disease and provide the rational for therapeutically targeting 4 integrin.