INVOLVEMENT OF RAF-1/MEK/ERK1/2 SIGNALING PATHWAY IN ZINC-INDUCED INJURY IN RAT RENAL CORTICAL SLICES

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  • KOHDA Yuka
    Division of Pharmacology, Osaka University of Pharmaceutical Sciences
  • MATSUNAGA Yoshiko
    Division of Pharmacology, Osaka University of Pharmaceutical Sciences
  • SHIOTA Ryugo
    Division of Pharmacology, Osaka University of Pharmaceutical Sciences
  • SATOH Tomohiko
    Division of Pharmacology, Osaka University of Pharmaceutical Sciences
  • KISHI Yuko
    Division of Pharmacology, Osaka University of Pharmaceutical Sciences
  • KAWAI Yoshiko
    Division of Pharmacology, Osaka University of Pharmaceutical Sciences
  • GEMBA Munekazu
    Division of Pharmacology, Osaka University of Pharmaceutical Sciences

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Zinc is an essential nutrient that can also be toxic. We have previously reported that zinc-related renal toxicity is due, in part, to free radical generation in the renal epithelial cell line, LLC-PK1 cells. We have also shown that an MEK1/2 inhibitor, U0126, markedly inhibits zinc-induced renal cell injury. In this study, we investigated the role of an upstream MEK/ERK pathway, Raf-1 kinase pathway, and the transcription factor and ERK substrate Elk-1, in rat renal cortical slices exposed to zinc. Immediately after preparing slices from rat renal cortex, the slices were incubated in medium containing Raf-1 and MEK inhibitors. ERK1/2 and Elk-1 activation were determined by Western blot analysis for phosphorylated ERK (pERK) 1/2 and phosphorylated Elk-1 (pElk-1) in nuclear fractions prepared from slices exposed to zinc. Zinc caused not only increases in 4-hydroxynonenal (4-HNE) modified protein and lipid peroxidation, as an index of oxidant stress, and decreases in PAH accumulation, as that of renal cell injury in the slices. Zinc also induced a rapid increase in ERK/Elk-1 activity accompanied by increased expressions of pERK and pElk-1 in the nuclear fraction. A Raf-1 kinase inhibitor and an MEK1/2 inhibitor U0126 significantly attenuated zinc-induced decreases PAH accumulation in the slices. The Raf-1 kinase inhibitor and U0126 also suppressed ERK1/2 activation in nuclear fractions prepared from slices treated with zinc. The present results suggest that a Raf-1/MEK/ERK1/2 pathway and the ERK substrate Elk-1 are involved in free radical-induced injury in rat renal cortical slices exposed to zinc.<br>

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