Genetic Deletion of Diacylglycerol Lipase-α, an Endocannabinoid-Producing Enzyme, Protects Against Cisplatin-Induced Nephrotoxicity

Background: Cisplatin is a potent and widely used anticancer drug for various solid tumors. However, kidney damage is the primary dose-limiting toxicity of cisplatin treatment. Emerging evidence indicates that the endocannabinoid system, including 2-arachidonoylglycerol (2-AG) and anandamide (AEA), and their cannabinoid receptors, contributes to different kidney diseases. However, little is known about the roles of their metabolic enzymes in kidney damage, including cisplatin nephrotoxicity. Considerable levels of renal 2-AG have been detected and dramatically increased in different kidney damage, indicating the potential role of its biosynthetic enzymes diacylglycerol lipases (DAGLs) in kidney damage. This study tested the hypothesis that the genetic deletion DAGLα protects the kidneys against cisplatin nephrotoxicity. Methods: A repeated low-dose cisplatin nephrotoxicity mouse model, which mimics the clinical dosing regimen used in patients, was employed. DAGLα knockout (KO) mice and their wild-type (WT) littermate controls were administered either vehicle or cisplatin (10 mg/kg, i.p. once weekly for 4 weeks). Results: KO-cisplatin mice showed a marked reduction in blood urea nitrogen (BUN) levels (44.8±5.25 mg/dL) compared to WT-cisplatin mice (100.9±8.6 mg/dL, p<0.05), while BUN levels remained low in vehicle-treated WT and KO mice (33.8±1.15 and 35.7±3.74 mg/dL, respectively). Plasma creatinine levels were significantly lower in KO-cisplatin mice (0.41±0.07 mg/dL) compared to WT-cisplatin mice (1.04±0.09 mg/dL, p<0.05), with no significant difference between vehicle groups (0.31±0.06 and 0.35±0.01 mg/dL for WT and KO, respectively). Histological evaluation using PAS staining revealed significantly reduced tubular injury in KO-cisplatin mice (injury score: 0.9) compared to WT-cisplatin mice (score: 2.6, p < 0.05), while WT- and KO-vehicle showed no injury (score: 0). Western blot analysis demonstrated a significant increase in kidney injury molecule-1 in WT-cisplatin mice (1.6-fold increase relative to vehicle groups), which was significantly attenuated in KO-cisplatin mice (0.7-fold increase relative to vehicle groups; p< 0.05). Conclusion: The results suggest that inactivation of DGLα prevents cisplatin nephrotoxicity and that targeting DAGLα may serve as a novel strategy for cisplatin nephrotoxicity. Funding: Other NIH Support - NCI