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1 Department of Medicine, Division of Nephrology, UMDNJ-New Jersey Medical School, Newark, New Jersey, USA
* To whom correspondence should be addressed. E-mail: Meggslg{at}umdnj.edu.
The activated IGF-1R protects cells from a wide range of apoptotic stimuli. Hyperglycemia promotes the intracellular generation of superoxide anion and hydrogen peroxide, both of which have been linked to the activation of the mitochondrial apoptosis program. Here, we report for the first time that ligand activation of the IGF-1R, protects normal human mesangial cells and SV40 murine mesangial cells, from the glycol-oxidant induced apoptosis program. The IGF-1R antiapoptosis program was dependent upon the recruitment of both Akt/PKB and the ERK subfamily of mitogen activated protein kinases. IGF-1 treatment also protected the redox potential of mesangial cells maintained at high ambient glucose concentration, by inhibiting the generation of reactive oxygen intermediates and preserving mitochondrial transmembrane potential. IGF-1R survival signals targeted the Bcl-2 family of proteins to protect against glucose induced apoptosis and oxidative stress. IGF-1 treated cells exhibited; a decrease in the Bax/Bcl-2 ratio; increased phosphorylation/inactivation of Bad at Ser112 and Ser136; inhibition of cytochrome-c release; perturbations directionally opposed to the initiation of the apoptosis program. In addition, we demonstrate IGF-1R activated ERK signaling modules, phosphorylate Ser112 of the mitochondrial Bad protein, establishing a direct link between surface IGF-1R and the survival program in mitochondria. Our findings indicate that in mesangial cells maintained at high ambient glucose concentration, IGF-1 activates a survival program that maintains the integrity of mitochondria and prevents the expression of the genetic program for apoptosis.
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