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Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
Submitted 28 August 2002 ; accepted in final form 31 March 2003
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-
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.
Fas; tumor necrosis factor receptor 1; reactive oxygen species; apoptosis; necrosis
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