Knockout of fatty acid amide hydrolase (FAAH) gene attenuates cisplatin-induced nephrotoxicity in mice

Cisplatin, a platinum-containing drug, is widely used in cancer therapy for a variety of solid tumors. However, acute kidney injury (AKI) is the primary dose-limiting toxicity of cisplatin treatment, which often requires discontinuation of the treatment. Recently, the endocannabinoid system including anandamide (AEA) and 2-arachidonoylglycerol (2AG) and their cannabinoid receptors (CBs) has been documented to play important roles in renal function and participate in different kidney diseases. However, little is known about roles of their metabolic enzymes in kidney damages, including cisplatin nephrotoxicity. Inhibition of FAAH, the primary enzyme for the degradation of AEA, has been reported to elicit anti-inflammatory effects. The current study tested the hypothesis that inhibition of FAAH attenuates cisplatin-induced acute kidney injury. Male wild type C57BL6 (WT) and Faah-/- mice were subjected to a single dose of intraperitoneal injection of cisplatin (30 mg/kg) or saline as vehicle and sacrificed 72 hours later. In comparison with WT-vehicle mice, Faah-/- mice showed pronounced reduction of blood urea nitrogen (BUN) (mean: 23.8 ±1.24, 156.6±15.2, and 81.8±12.25 mg/dL in WT-vehicle, WT-cisplatin, and Faah-/- -cisplatin mice, respectively, p<0.001) and plasma creatinine level (mean: 1.18 ± 0.12, 3.30 ± 0.46, and 1.45±0.46 mg/dL in WT-vehicle, WT- cisplatin, and Faah-/- - cisplatin mice, respectively, p<0.01) after cisplatin-induced nephrotoxicity. Semi-quantitative histologic analysis by Periodic acid-Schiff (PAS) staining demonstrated that cisplatin-induced kidney injuries were significantly attenuated in Faah-/- mice especially in tubular structure (tubular injury score: 0 in WT-vehicle, 3.6 in WT- cisplatin, and 2.3 in Faah-/- - cisplatin mice, respectively, p<0.001). Western blot analysis revealed that in comparison with WT-vehicle mice, WT-cisplatin mice showed significant upregulation of kidney injury molecule-1 (KIM-1), which was remarkably reduced in Faah-/- mice (1.6-fold versus 0.8-fold compared to the WT-vehicle group, p<0.05). These data suggest that inactivation of FAAH prevents nephrotoxicity caused by cisplatin treatment and that targeting FAAH may provide a novel strategy to mitigate cisplatin-induced nephrotoxicity. © FASEB.