EGFR-dependent ERK activation triggers hydrogen peroxide-induced apoptosis in OK renal epithelial cells.
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.
Lee
Ju Suk
JS
Department of Pediatrics, College of Medicine, Pusan National University, 602-739 Pusan, South Korea.
Kim
Su Yung
SY
Kwon
Chae Hwa
CH
Kim
Yong Keun
YK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000633:toxicity*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D051336:Mitochondrial Membranes / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology; D009893:Opossums; D016877:Oxidants / Q000633:toxicity*; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines; D014162:Transfection; D020032:Tyrphostins / Q000494:pharmacology
C412373:AG 1879; D002070:Butadienes; D004791:Enzyme Inhibitors; D005419:Flavonoids; D009570:Nitriles; D016877:Oxidants; D011743:Pyrimidines; D011799:Quinazolines; D020032:Tyrphostins; C113580:U 0126; C101044:RTKI cpd; D006861:Hydrogen Peroxide; C483803:Egfr protein, rat; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one