The cannabinoids arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG) are endogenous ligands for the cannabinoid receptors including CB1 and CB2 subtypes. The endocannabinoid system (ECS) is typically associated with regulation of metabolic balance and appetite, although CB1 receptors (CB1R) may contribute to diabetic renal injury while CB2R are protective. The hypertensive mRen2.Lewis (mRen2) females have less renal injury than the males; however, diabetic female mRen2 lack this protection and show comparable indices of injury to the diabetic males. The present study addressed whether female and male diabetic mRen2 exhibit similar alterations in the renal ECS. Diabetes was induced with a single dose of streptozotocin (STZ at 65 mg/kg; ip). Cortical content of AEA and 2-AG was quantified by UPLC MS/MS. Receptor levels and the metabolizing enzymes for AEA (FAAH) and 2-AG (MAGL) were quantified by protein immunoblot. Basal 2-AG content was higher in male versus female mRen2, and significantly increased in both diabetic females and males (figure, n=6) while AEA was unchanged. Cortical Ang II correlated to 2-AG [p<0.01; r = 0.89]. CB1R protein expression was higher in female diabetic mRen2 but unchanged in the males (figure, n=4). CB2R expression was lower in the male diabetics [p<0.01; n=4], but not changed in females. MAGL expression was >70% lower in female diabetics compared to controls [p<0.05; n=4] while FAAH was not changed. Elements of the renal ECS are differentially regulated in the diabetic mRen2. Higher expression of both 2-AG and CB1R, but reduced MAGL (females) and CB2R (males) may contribute to the development and progression of renal injury in this model.