Antioxidant ameliorates cisplatin-induced renal tubular cell death through inhibition of death receptor-mediated pathways

Kazuhiko Tsuruya, Masanori Tokumoto, Toshiharu Ninomiya, Makoto Hirakawa, Kohsuke Masutani, Masatomo Taniguchi, Kyoichi Fukuda, Hidetoshi Kanai, Hideki Hirakata, Mitsuo Iida

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Abstract

We have recently demonstrated the direct involvement of the death receptor-mediated apoptotic pathways in cisplatin-induced renal tubular cell (RTC) death. Reactive oxygen species are thought to be a major cause of cellular damage in such injury. The aim of this study was to examine the mechanism through which antioxidants ameliorate cisplatin-induced RTC death, with special emphasis on death receptor-mediated apoptotic pathways. Cisplatin was added to cultures of normal rat kidney (NRK52E) cells or injected in rats. NRK52E cells and rats were also treated with dimethylthiourea (DMTU), a hydroxyl radical scavenger. We then examined the mRNA levels of death ligands and receptors, caspase-8 activity, cell viability, cell death, renal function, and histological alterations. RT-PCR indicated cisplatin-induced upregulation of Fas, Fas ligand, and TNF-α mRNAs and complete inhibition by DMTU in vitro and in vivo. Cisplatin increased caspase-8 activity of NRK52E cells, and DMTU prevented such activation. Exposure to cisplatin reduced viability of NRK52E cells, examined by WST-1 assay, and increased apoptosis and necrosis of the cells, examined by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and fluorescence-activated cell sorter analysis. DMTU abrogated cisplatin-induced changes in cell viability and apoptosis and/or necrosis. Cisplatin-induced renal dysfunction and histological damage were also prevented by DMTU. DMTU did not hinder cisplatin incorporation into RTCs. Our results suggest that antioxidants can ameliorate cisplatin-induced acute renal failure through inactivation of the death receptor-mediated apoptotic pathways.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume285
Issue number2 54-2
Publication statusPublished - Aug 1 2003

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Keywords

  • Apoptosis
  • Fas
  • Necrosis
  • Reactive oxygen species
  • Tumor necrosis factor receptor 1

ASJC Scopus subject areas

  • Physiology

Cite this

Tsuruya, K., Tokumoto, M., Ninomiya, T., Hirakawa, M., Masutani, K., Taniguchi, M., ... Iida, M. (2003). Antioxidant ameliorates cisplatin-induced renal tubular cell death through inhibition of death receptor-mediated pathways. American Journal of Physiology - Renal Physiology, 285(2 54-2).