Oxidative Stress-mediated Mesangial Cell Proliferation Requires RAC-1/Reactive Oxygen Species Production and β4 Integrin Expression

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 ␤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.Abnormalities in lipoprotein metabolism are commonly observed in patients with renal disease. Specifically, hyperlipidemia and glomerular lipid deposition of atherogenic lipoproteins (low density lipoproteins (LDL), 2 and their oxidized variants, ox-LDL) are implicated in key pathobiological processes involved in the development of glomerular diseases, including mesangial cell (MC) hypercellularity (1). The relevance of mitogen intracellular signaling in mesangial proliferative disease has only recently been recognized (2). Indeed, accumulation of atherogenic lipoproteins within the glomerulus, by activating membrane receptor protein-tyrosine kinases (RPTK), such as the epidermal growth factor receptor (EGFR), triggers MAPK cascades leading to cyclin/cyclin-dependent kinase activation of DNA synthesis and MC proliferation (2). Moreover, in smooth muscle cells, ox-LDL (3) has been shown to trigger the phosphatidylinositol 3-kinase/Akt signaling pathway (4). These data thus suggest that atherogenic lipoproteins may act as one of the major endogenous modulators for mitogenic signaling response within the glomerulus.Although superoxide anions and hydrogen peroxide are generally considered to be toxic, recent evidence suggests that the production of the reactive oxygen species (ROS) might be an integral component of membrane receptor signaling (5). In mammalian cells, a vast array of intracellular stimuli have been shown to induce a transient increase in the intracellular ROS concentrations, and specific inhibition of ROS generation results in a complete blockage of stimulant-dependent signaling (5). In particular, growth factor-mediated ROS generation seems to be necessary for propagation of downstream mitogenic and antiapoptotic signals (5).Rho family GTPases are imp...

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