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Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, South Carolina 29425
Submitted 12 August 2003 ; accepted in final form 25 December 2003
Although oxidative stress activates epidermal growth factor receptor (EGFR), ERK1/2, and Akt in a number of cell types, the mechanisms by which oxidative stress activates these kinases are not well defined in renal epithelial cells. Exposure of primary cultures of rabbit renal proximal tubular cells to hydrogen peroxide (H2O2) stimulated Src, EGFR, ERK1/2, and Akt activation in a time-dependent manner as determined by the phosphorylation of each protein. The Src inhibitor PP1 completely blocked EGFR, ERK1/2, and Akt phosphorylation following H2O2 exposure. In contrast, blockade of the EGFR by AG1478 inhibited phosphorylation of ERK1/2 but not Src or Akt phosphorylation following H2O2 exposure. Exogenous EGF stimulated EGFR, ERK1/2, and Akt activation and the EGFR inhibitor blocked phorphorylation of ERK1/2 and Akt. The presence of PP1, but not AG1478, significantly accelerated H2O2-induced cell death. These results suggest that Src mediates H2O2-induced EGFR transactivation. H2O2- and EGF-induced ERK1/2 activation is mediated by EGFR, whereas Akt is activated by Src independent of EGFR following H2O2 exposure. Src-mediated EGFR transactivation contributes to a survival response following oxidative injury.
heparin-binding epidermal growth factor; phosphatidylinositol 3-kinase; renal proximal tubule
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