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

Research output: Contribution to journalArticle

89 Citations (Scopus)

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
Pages (from-to)F208-F218
JournalAmerican Journal of Physiology - Renal Physiology
Volume285
Issue number2 54-2
Publication statusPublished - Aug 1 2003

Fingerprint

Death Domain Receptors
Cisplatin
Cell Death
Antioxidants
Kidney
Cell Survival
Caspase 8
Necrosis
Apoptosis
Messenger RNA
Fas Ligand Protein
DNA Nucleotidylexotransferase
Acute Kidney Injury
Hydroxyl Radical
1,3-dimethylthiourea
Reactive Oxygen Species
Up-Regulation
Fluorescence
Ligands
Polymerase Chain Reaction

All Science Journal Classification (ASJC) codes

  • Physiology
  • Urology

Cite this

Antioxidant ameliorates cisplatin-induced renal tubular cell death through inhibition of death receptor-mediated pathways. / Tsuruya, Kazuhiko; Tokumoto, Masanori; Ninomiya, Toshiharu; Hirakawa, Makoto; Masutani, Kohsuke; Taniguchi, Masatomo; Fukuda, Kyoichi; Kanai, Hidetoshi; Hirakata, Hideki; Iida, Mitsuo.

In: American Journal of Physiology - Renal Physiology, Vol. 285, No. 2 54-2, 01.08.2003, p. F208-F218.

Research output: Contribution to journalArticle

Tsuruya, K, Tokumoto, M, Ninomiya, T, Hirakawa, M, Masutani, K, Taniguchi, M, Fukuda, K, Kanai, H, Hirakata, H & Iida, M 2003, 'Antioxidant ameliorates cisplatin-induced renal tubular cell death through inhibition of death receptor-mediated pathways', American Journal of Physiology - Renal Physiology, vol. 285, no. 2 54-2, pp. F208-F218.
Tsuruya, Kazuhiko ; Tokumoto, Masanori ; Ninomiya, Toshiharu ; Hirakawa, Makoto ; Masutani, Kohsuke ; Taniguchi, Masatomo ; Fukuda, Kyoichi ; Kanai, Hidetoshi ; Hirakata, Hideki ; Iida, Mitsuo. / Antioxidant ameliorates cisplatin-induced renal tubular cell death through inhibition of death receptor-mediated pathways. In: American Journal of Physiology - Renal Physiology. 2003 ; Vol. 285, No. 2 54-2. pp. F208-F218.
@article{ff172e70ebbc46738d99089589a58908,
title = "Antioxidant ameliorates cisplatin-induced renal tubular cell death through inhibition of death receptor-mediated pathways",
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.",
author = "Kazuhiko Tsuruya and Masanori Tokumoto and Toshiharu Ninomiya and Makoto Hirakawa and Kohsuke Masutani and Masatomo Taniguchi and Kyoichi Fukuda and Hidetoshi Kanai and Hideki Hirakata and Mitsuo Iida",
year = "2003",
month = "8",
day = "1",
language = "English",
volume = "285",
pages = "F208--F218",
journal = "American Journal of Physiology - Renal Fluid and Electrolyte Physiology",
issn = "1931-857X",
publisher = "American Physiological Society",
number = "2 54-2",

}

TY - JOUR

T1 - Antioxidant ameliorates cisplatin-induced renal tubular cell death through inhibition of death receptor-mediated pathways

AU - Tsuruya, Kazuhiko

AU - Tokumoto, Masanori

AU - Ninomiya, Toshiharu

AU - Hirakawa, Makoto

AU - Masutani, Kohsuke

AU - Taniguchi, Masatomo

AU - Fukuda, Kyoichi

AU - Kanai, Hidetoshi

AU - Hirakata, Hideki

AU - Iida, Mitsuo

PY - 2003/8/1

Y1 - 2003/8/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0038486911&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0038486911&partnerID=8YFLogxK

M3 - Article

C2 - 12684229

AN - SCOPUS:0038486911

VL - 285

SP - F208-F218

JO - American Journal of Physiology - Renal Fluid and Electrolyte Physiology

JF - American Journal of Physiology - Renal Fluid and Electrolyte Physiology

SN - 1931-857X

IS - 2 54-2

ER -