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1 Department of Medicine, University of Arkansas For Medical Sciences, Little Rock, AR, USA; Department of Biochemistry, University of Arkansas for Medical Sciences, Little Rock, AR, USA
2 Department of Medicine, University of Arkansas For Medical Sciences, Little Rock, AR, USA
* To whom correspondence should be addressed. E-mail: Kaushalgurp{at}uams.edu.
Cytotoxicity to renal tubular epithelial cells (RTE) is dependent on the relative response of cell survival and cell death signals triggered by the injury. Forkhead transcription factors, Bcl-2 family member Bad, and mitogen-activated protein kinases are regulated by phosphorylation that plays crucial roles in determining cell fate. We examined the role of phosphorylation of these proteins in regulation of H2O2-induced caspase activation in RTE. The phosphorylation of FKHR, FKHRL, and Bcl-2 family member Bad were markedly increased in response to oxidant injury, and this increase was associated with elevated levels of basal phosphorylation of Akt/protein kinase B. PI-3 kinase inhibitors abolished this phosphorylation and also decreased expression of antiapoptotic proteins Bcl-2 and BclxL. Inhibition of phosphorylation of forkhead proteins resulted in a marked increase in proapoptotic protein Bim. These downstream effects of PI-3 kinase inhibition promoted the oxidantinduced activation of caspase-3 and -9, but not caspase-8 and -1. The impact of enhanced activation of caspases by PI-3 kinase inhibition was reflected on accelerated oxidant-induced cell death. Oxidant stress also induced marked phosphorylation of ERK 1/2, P38, and JNK kinases. Inhibition of ERK 1/2 phosphorylation but not P38 and JNK kinase increased caspase-3 and -9 activation; however, this activation was far less than induced by inhibition of Akt phosphorylation. Thus, Akt - mediated phosphorylation pathway, ERK signaling and the antiapoptotic Bcl-2 proteins distinctly regulate caspase activation during oxidant injury to RTE. These studies suggest that enhancing renal-specific survival signals may lead to preservation of renal function during oxidant injury.
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