Cisplatin-induced oxidative stress stimulates renal fas ligand shedding

Hitesh Soni, Damian Kaminski, Raja Shekhar Gangaraju, Adebowale Adebiyi

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Acute kidney injury (AKI), a significant complication of cisplatin chemotherapy is associated with reactive oxygen species (ROS)-dependent renal cell death, but the cellular targets of ROS in cisplatin nephrotoxicity are not fully resolved. Here, we investigated cisplatin-induced oxidative renal damage and tested the hypothesis that ROS-dependent shedding of death activator Fas ligand (FasL) occurs in cisplatin nephropathy. We show that intraperitoneal injection of sulfobutyl ether-β-cyclodextrin (Captisol™)-solubilized cisplatin elevated the level of lipid peroxidation product malondialdehyde in mouse kidneys and urinary concentration of oxidative DNA damage biomarker 8-hydroxy-2’-deoxyguanosine. Cisplatin increased mouse kidney-to-body weight ratio and the plasma or urinary levels of predictive biomarkers of AKI, including creatinine, blood urea nitrogen, microalbumin, neutrophil gelatinase-associated lipocalin, and cystatin C. Histological analysis and dUTP nick end labeling of kidney sections indicated tubular injury and renal apoptosis, respectively in cisplatin-treated mice. Whereas the plasma concentration of soluble FasL (sFasL) was unaltered, urinary sFasL was increased~4-fold in cisplatin-treated mice. Real-time quantitative live-cell imaging and lactate dehydrogenase assay showed that cisplatin stimulated caspase 3/7 activation and cytotoxicity in a human proximal tubule epithelial cell line which were attenuated by inhibitors of the FasL/Fas system and poly [ADP-ribose] polymerase-1. Moreover, TEMPOL, an intracellular free radical scavenger mitigated cisplatin-induced renal oxidative stress and injury, AKI biomarker and urinary sFasL elevation, and proximal tubule cell death. Our findings indicate that cisplatin-induced oxidative stress triggers the shedding of membrane-bound FasL to sFasL in the kidney. We demonstrate that cisplatin elicits nephrotoxicity by promoting FasL/Fas-dependent oxidative renal tubular cell death.

Original languageEnglish (US)
Pages (from-to)314-322
Number of pages9
JournalRenal Failure
Volume40
Issue number1
DOIs
StatePublished - Oct 15 2018

Fingerprint

Fas Ligand Protein
Cisplatin
Oxidative Stress
Kidney
Acute Kidney Injury
Reactive Oxygen Species
Cell Death
Biomarkers
Caspase 7
Cystatin C
Free Radical Scavengers
Blood Urea Nitrogen
Wounds and Injuries
Cyclodextrins
Intraperitoneal Injections
Malondialdehyde
L-Lactate Dehydrogenase
Caspase 3
Ether
Lipid Peroxidation

All Science Journal Classification (ASJC) codes

  • Critical Care and Intensive Care Medicine
  • Nephrology

Cite this

Cisplatin-induced oxidative stress stimulates renal fas ligand shedding. / Soni, Hitesh; Kaminski, Damian; Gangaraju, Raja Shekhar; Adebiyi, Adebowale.

In: Renal Failure, Vol. 40, No. 1, 15.10.2018, p. 314-322.

Research output: Contribution to journalArticle

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