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

  • Organ Toxicity and Mechanisms
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Abstract

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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Acknowledgement

This work was supported by grant R01-2002-000-00460-0 (2002) from the Basic Research Program of the Korean Science & Engineering foundation.

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Authors and Affiliations

  1. Department of Pediatrics, College of Medicine, Pusan National University, 602-739, Pusan, South Korea

    Ju Suk Lee & Su Yung Kim

  2. Department of Physiology, College of Medicine, Pusan National University, 602-739, Pusan, South Korea

    Chae Hwa Kwon & Yong Keun Kim

  3. Medical Research Institute, College of Medicine, Pusan National University, 602-739, Pusan, South Korea

    Su Yung Kim & Yong Keun Kim

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  1. Ju Suk Lee
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Correspondence to Yong Keun Kim.

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Lee, J.S., Kim, S.Y., Kwon, C.H. et al. EGFR-dependent ERK activation triggers hydrogen peroxide-induced apoptosis in OK renal epithelial cells. Arch Toxicol 80, 337–346 (2006). https://doi.org/10.1007/s00204-005-0052-2

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  • DOI: https://doi.org/10.1007/s00204-005-0052-2

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