Abstract
Cisplatin is a potent first-line therapy for many solid malignancies, such as breast, ovarian, lung, testicular, and head and neck cancer. However, acute kidney injury (AKI) is a major dose-limiting toxicity in cisplatin therapy, which often hampers the continuation of cisplatin treatment. The endocannabinoid system, consisting of anandamide (AEA) and 2-arachidonoylglycerol and cannabinoid receptors, participates in different kidney diseases. Inhibition of fatty acid amide hydrolase (FAAH), the primary enzyme for the degradation of AEA and AEA-related N-acylethanolamines, elicits anti-inflammatory effects; however, little is known about its role in cisplatin nephrotoxicity. The current study tested the hypothesis that genetic deletion of Faah mitigates cisplatin-induced AKI. Male wild-type C57BL6 (WT) and Faah−/− mice were administered a single dose of intraperitoneal injection of cisplatin (30 mg/kg) and euthanatized 72 hours later. Faah−/− mice showed a reduction of cisplatin-induced blood urea nitrogen, plasma creatinine levels, kidney injury markers, and tubular damage in comparison with WT mice. The renal protection from Faah deletion was associated with enhanced tone of AEA-related N-acylethanolamines (palmitoylethanolamide and oleoylethanolamide), attenuated nuclear factor-κB/p65 activity, DNA damage markers p53 and p21, and decreased expression of the inflammatory cytokine interleukin-1β, as well as infiltration of macrophages and leukocytes in the kidneys. Notably, a selective FAAH inhibitor (PF-04457845) did not interfere with or perturb the antitumor effects of cisplatin in two head and neck squamous cell carcinoma cell lines, HN30 and HN12. Our work highlights that FAAH inactivation prevents cisplatin-induced nephrotoxicity in mice and that targeting FAAH could provide a novel strategy to mitigate cisplatin-induced nephrotoxicity.
SIGNIFICANCE STATEMENT Mice lacking the Faah gene are protected from cisplatin-induced inflammation, DNA damage response, tubular damage, and kidney dysfunction. Inactivation of FAAH could be a potential strategy to mitigate cisplatin-induced nephrotoxicity.
Footnotes
- Received August 29, 2022.
- Accepted December 21, 2022.
This research was supported in part by the National Institutes of Health (NIH) National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, and National Cancer Institute [Grant R01-HL145163, DK107991, R21-CA274012] (to N.L.) and [Grant R01-CA239706, CA206028, CA260819] (to D.A.G.). Services and products in support of the research project were generated by the Virginia Commonwealth University Cancer Mouse Models Core Laboratory, supported, in part, with funding to the Massey Cancer Center from NIH-NCI Cancer Center Support [Grant P30-CA016059]. Mutant mice in support of the research project were generated by the Virginia Commonwealth University Cancer Transgenic/Knock-Out Mouse Shared Resource supported in part by funding from NIH National Institute on Drug Abuse [Grant P30-DA033934] (to A.H.L.).
No author has an actual or perceived conflict of interest with the contents of this article.
- Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics
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