Oxidative stress-mediated mesangial cell proliferation requires RAC-1/reactive oxygen species production and beta4 integrin expression.
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 beta4 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 beta4 integrin.
Dentelli
Patrizia
P
Department of Internal Medicine, University of Torino, Corso Dogliotti 14, 10126 Torino, Italy.
Rosso
Arturo
A
Zeoli
Annarita
A
Gambino
Roberto
R
Pegoraro
Luigi
L
Pagano
Gianfranco
G
Falcioni
Rita
R
Brizzi
Maria Felice
MF
D002470:Cell Survival / Q000187:drug effects; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000628:therapy; D066246:ErbB Receptors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D039663:Integrin beta4 / Q000096:biosynthesis*; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D050527:Mesangial Cells; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D039663:Integrin beta4; D008077:Lipoproteins, LDL; C107953:RAC1 protein, human; D017382:Reactive Oxygen Species; C099252:oxidized low density lipoprotein; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020830:rac1 GTP-Binding Protein