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.
Highlights
Cisplatin and its platinum analogs are potent chemotherapeutic drugs used for the treatment of a wide variety of malignant tumors, including bladder, ovarian, cervical, testicular, lung, and head and neck cancers [1,2,3]
We investigated cisplatin-induced oxidative renal damage and tested the hypothesis that reactive oxygen species (ROS)-dependent renal membrane-bound FasL (mFasL) shedding occurs in cisplatin nephropathy
The salient findings of our study include 1) SBE-b-CD solubilization retains the nephrotoxic effect of cisplatin in vivo and in vitro, 2) cisplatin induces Fas ligand (FasL)-dependent renal tubular cell death via oxidative stress, and 3) cisplatininduced oxidative stress stimulates renal soluble FasL (sFasL) production
Summary
Cisplatin and its platinum analogs are potent chemotherapeutic drugs used for the treatment of a wide variety of malignant tumors, including bladder, ovarian, cervical, testicular, lung, and head and neck cancers [1,2,3]. Cisplatin is a potent chemotherapeutic agent, its use is limited by significant side effects, especially organ toxicity. Cardiotoxicity, ototoxicity, hepatotoxicity, and nephrotoxicity [4,5,6,7]. Acute kidney injury (AKI) represents a noticeable adverse effect of cisplatin therapy as cisplatin accumulates in the kidney and causes a decline in vascular, glomerular, and tubular functions [4,5,6,7]. Given the common nephrotoxic adverse effect of cisplatin chemotherapy, elucidation of the cellular mechanisms that underlie cisplatin-induced AKI has been the focus of intense research
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