Mitigation of cisplatin-induced acute kidney injury through oral administration of fatty acid amide hydrolase inhibitor PF-04457845.

Fatty acid amide hydrolase (FAAH) serves as the primary enzyme responsible for degrading the endocannabinoid anandamide. Inhibition of FAAH, either through pharmacological means or genetic manipulation, can effectively reduce inflammation in various organs, including the brain, colon, heart, and kidneys. Infusion of a FAAH inhibitor into the kidney medulla induces diuretic and natriuretic effects. Moreover, FAAH knockout mice show protection against both post renal ischemia/reperfusion injury and cisplatin-induced acute kidney injury (AKI), although through distinct mechanisms. This study tested the hypothesis that pharmacological inhibition of FAAH activity mitigates cisplatin-induced AKI, thus, exploring potential renoprotective mechanism. Male wild-type C57BL/6J were administered an oral gavage of a FAAH inhibitor (PF-04457845, 5 mg/kg) or vehicle (10% PEG200+5% Tween 80+normal saline) at 72, 48, 24, and 2 hours before and 24 and 48 hours after a single intraperitoneal injection of cisplatin (25 mg/kg). Mice were euthanized 72 hours after cisplatin treatment. Compared with vehicle-treated mice, PF-04457845-treated mice showed a decrease of cisplatin-induced plasma creatinine, blood urea nitrogen levels, kidney injury biomarkers (neutrophil gelatinase-associated lipocalin and kidney injury molecule-1) and renal tubular damage. The renal protection from oral gavage of PF-04457845 against cisplatin-induced nephrotoxicity was associated with an enhanced endocannabinoid anandamide tone and reduced levels of DNA damage response biomarkers p53 and p21. Our work demonstrated that PF-04457845 effectively alleviates cisplatin-induced nephrotoxicity in mice, underscoring the potential of oral administration of a FAAH inhibitor as a novel strategy to prevent cisplatin nephrotoxicity. SIGNIFICANCE STATEMENT: Oral administration of the fatty acid amide hydrolase (FAAH) inhibitor, PF-04457845, reduced cisplatin-induced DNA damage response, tubular damage, and kidney dysfunction. Inhibition of FAAH represents a promising approach to prevent cisplatin-induced nephrotoxicity.