JP4-039 Mitigates Cisplatin-Induced Nephrotoxicity and Prevents AKI

Background: Cisplatin is a commonly used highly effective therapeutic in cancer treatment.However, its use is limited by its nephrotoxicity which occurs in about 30 percent of patients receiving cisplatin chemotherapy.Sincecisplatin induced AKI remains a major unmet medical need without any pharmacological interventions, we decided to explore the nephroprotective effects of a novel mitochondria-targeted reactive oxygen species (ROS) and electron scavenger JP4-039. Methods: Male mice (129Sv-Elite, Charles River)were +/- treated with JP4-039 (10 mg/kg) 24 hours before or after cisplatin (10 mg/kg) injection, and kidneys analyzed 72 hours later for functional and molecular changes.Histological analysis was performed using PAS staining. Markers of tubular injury, DNA damage, lipid peroxidation, ROS and apoptosis were assessed by immunofluorescence and immunohistochemistry. Blood urea nitrogen was used to assess kidney function and qPCR was used to assess changes in gene expression. Results: Asingle dose of cisplatin induced significant BUN elevation and kidney injury (KIM1, NGAL expression) in 129Sv-Elite mice after 72 hours, indicative of AKI. These pathologic changes were absent in mice who had received pre- or post-cisplatin JP4-039 injections, demonstrating a prevention of AKI. In addition, treatment with JP4-039 mitigated kidney morphology and histology in cisplatin-treated mice. Specifically, JP4-039 reduced the levels of tissue oxidative lesions, including oxidative DNA damage (8-OHdG) and lipid peroxidation (4-HNE), and mitigated tubular apoptosis. Mechanistically, we propose that JP4-039 exerts its renoprotective action by suppressing the NRF2 pathway, as the expression of NRF2 and its target genes (Nqo1, Txnrd1) was downregulated in JP4-039 kidneys. Further, JP4-039 attenuated the expression of various inflammatory cytokines associated with AKI in cisplatin injured kidneys. Conclusion: Our data demonstrate that the novel antioxidant compound JP4-039 protects the kidneys from cisplatin induced AKI by suppressing tubular oxidative stress and inhibiting proinflammatory and proapoptotic pathways.Moreover, our studies show that JP4-039 can be administered both as a preventative or interventional therapy to suppress AKI induction. Funding: NIDDK Support