Regulation of caspase-3 and-9 activation in oxidant stress to RTE by forkhead transcription factors, Bcl-2 proteins, and MAP kinases

被引:58
作者
Kaushal, GP
Liu, L
Kaushal, V
Hong, XM
Melnyk, O
Seth, R
Safirstein, R
Shah, SV
机构
[1] Univ Arkansas Med Sci, Dept Biochem, Little Rock, AR 72205 USA
[2] Univ Arkansas Med Sci, Dept Med, Cent Arkansas Vet Healthcare Syst, Little Rock, AR 72205 USA
关键词
LLC-PK(1) cells; Akt phosphorylation; Bim; PI 3-kinase inhibitors;
D O I
10.1152/ajprenal.00391.2003
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
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 H(2)O(2)-induced caspase activation in RTE. The phosphorylation of FKHR, FKHRL, and Bcl-2 family member Bad was markedly increased in response to oxidant injury, and this increase was associated with elevated levels of basal phosphorylation of Akt/protein kinase B. Phosphoinositol ( 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 the proapoptotic protein Bim. These downstream effects of PI 3-kinase inhibition promoted the oxidant-induced 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 ERK1/2, P38, and JNK kinases. Inhibition of ERK1/2 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 the 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.
引用
收藏
页码:F1258 / F1268
页数:11
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