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1 Pharmaceutical sciences, medical university of south carolina, Charleston, South Carolina, United States
2 Surgery, Medical University of SC, Charleston, South Carolina, United States
3 Pharmaceutical Sciences, Medical University of SC, Charleston, South Carolina, United States
4 Department of Immunology, The Scripps Research Institute, La Jolla, California, United States
5 Pharmaceutical Sciences, Medical University of South Carolina, Charleston, South Carolina, United States
* To whom correspondence should be addressed. E-mail: zhuang{at}musc.edu.
Reactive oxygen species, including hydrogen peroxide, are generated during ischemia/reperfusion and are critically involved in acute renal failure. The present studies examined the role of the extracellular signal regulated kinase (ERK) pathway in hydrogen peroxide-induced renal proximal tubular cells (RPTC) apoptosis. Exposure of RPTC to 1 mM hydrogen peroxide resulted in apoptosis and activation of ERK1/2 and Akt. Pretreatment with the specific MEK inhibitors, U0126 and PD98059, or adenoviral infection with a construct that encodes a negative mutant of MEK1, protected cells against hydrogen peroxide induced apoptosis. In contrast, expression of constitutively active MEK1 enhanced hydrogen peroxide-induced apoptosis. Hydrogen peroxide induced activation of caspase-3 and phosphorylation of histone H2B at serine 14, a post-translational modification required for nuclear condensation, which also were blocked by ERK1/2 inhibition. Further, blockade of ERK1/2 resulted in an increase in Akt phosphorylation and blockade of Akt potentiated apoptosis and diminished the protective effect conferred by ERK inhibition in hydrogen peroxide-treated cells. Although Z-DEVD-FMK, a caspase-3 inhibitor, was able to inhibit histone H2B phosphorylation and apoptosis, it did not affect ERK1/2 phosphorylation. We suggest that ERK elicits apoptosis in epithelial cells by activating caspase-3 and inhibiting Akt pathways, and elicits nuclear condensation through caspase-3 and histone H2B phosophorylation during oxidant injury.
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