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

• Published in: Archives of toxicology 2006-06, Vol.80 (6), p.337-346
• Main Authors: Lee, Ju Suk, Kim, Su Yung, Kwon, Chae Hwa, Kim, Yong Keun
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Butadienes - pharmacology; Cell Line; Cell Survival - drug effects; Cellular biology; Dose-Response Relationship, Drug; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - metabolism; Flavonoids - pharmacology; Hydrogen Peroxide - toxicity; Kidney Tubules, Proximal - drug effects; Kidney Tubules, Proximal - enzymology; Kidney Tubules, Proximal - pathology; Kinases; MAP Kinase Kinase 1 - genetics; MAP Kinase Kinase 1 - metabolism; Membrane Potentials - drug effects; Mitochondrial Membranes - drug effects; Nitriles - pharmacology; Opossums; Oxidants - toxicity; Proteins; Pyrimidines - pharmacology; Quinazolines; Receptor, Epidermal Growth Factor - metabolism; Transfection; Tyrphostins - pharmacology
• ISSN: 0340-5761; 1432-0738
• DOI: 10.1007/s00204-005-0052-2

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.