EGFR-dependent ERK activation triggers hydrogen peroxide-induced apoptosis in OK renal epithelial cells

Department of Pediatrics, College of Medicine, Pusan National University, 602-739 Pusan, South Korea.
Archive für Toxikologie (Impact Factor: 5.98). 07/2006; 80(6):337-46. DOI: 10.1007/s00204-005-0052-2
Source: PubMed


Oxidative stress induces activation of extracellular signal-regulated kinase (ERK), a member of the mitogen-activated protein kinase families. However, it is unclear in renal epithelial cells whether the ERK activation is involved in cell survival or cell death in H2O2-treated cells. The present study was undertaken to determine the role of the ERK activation in H2O2-induced apoptosis of renal epithelial cells using opossum kidney (OK) cells, an established proximal tubular epithelial cell line. H2O2 resulted in a time- and dose-dependent apoptosis of OK cells. H2O2 treatment caused marked sustained activation of ERK. The ERK activation was prevented by PD98059 and U0126, inhibitors of ERK1/2 upstream kinase MEK1/2. Apoptosis caused by H2O2 was prevented by U0126. Transient transfection with constitutive active MEK1 increased the H2O2-induced apoptosis, whereas transfection with dominant-negative mutants of MEK1 decreased the apoptosis. H2O2 produced hyperpolarization of mitochondrial membrane potential and activation of caspases-3. H2O2-induced ERK activation was inhibited by the Src family selective inhibitor PP2 and the epidermal growth factor receptor inhibitor AG1478. The presence of AG1478, but not PP2, prevented H2O2-induced cell death. Taken together, our findings suggest that the ERK activation mediated by epidermal growth factor receptor plays an active role in inducing H2O2-induced apoptosis of OK cells and functions upstream of mitochondria-dependent pathway to initiate the apoptotic signal.

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    • "To investigate the molecular mechanism by which Sal B exerts its anti-apoptotic effects, the activation of MAPK was examined. An increasing body of evidence has shown that H2O2 stimulation increases extracellular signal-regulated kinase (ERK) activation and concomitant apoptosis [21], [22]. We performed the apoptosis analysis using U0126, a specific inhibitor of ERK upstream kinase MEK [23]. "
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