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-alpha 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.

Protective effect of pomegranate seed oil against cisplatin-induced nephrotoxicity in rat

“…Thus, oxidative stress and death receptor-mediated apoptotic cascades are considered to interact synergistically. 36,37 Nonsignificant alterations of renal MDA and thiol content may be due to low dose of cisplatin. PSO administration 1 h before cisplatin treatment significantly reduced the development of cisplatin-induced acute renal failure as evidenced by functional and histopathological findings.…”

Mobilization of Bone Marrow Cells by G-CSF Rescues Mice from Cisplatin-Induced Renal Failure, and M-CSF Enhances the Effects of G-CSF

“…However, dialysis itself cannot repair the RTEC. Some reagents, such as fosfomycin (34,35), anti-TNF (36), and antioxidants (37), have been reported to have the ability to protect RTEC from noxious substances. From our results, we suggest that the mobilization of BMC by G-CSF, etc., could become a new strategy for preventing not only acute renal failure as a result of the necrosis of RTEC but also the side effects of drugs on various organs.…”

Butein Ameliorates Renal Concentrating Ability in Cisplatin-Induced Acute Renal Failure in Rats

“…11,29) In the previous study, various antioxidant agents showed protective effect against renal injury induced by cisplatin in rats. [30][31][32] In summary, butein, a plant polyphenol, ameliorates renal concentrating ability via up-regulation of renal AQP 2 water channel in rats with cisplatin-induced ARF.…”