Chronic administration of AM251 improves albuminuria and renal tubular structure in obese rats

Abstract

Modulation of the endocannabinoid system as an anti-obesity therapeutic is well established; however, the direct effects of cannabinoid receptor 1 (CB 1) antagonism on renal function and structure in a model of diet-induced obesity (DIO) are unknown. The aim of this study was to characterise the renal effects of the CB 1 antagonist AM251 in a model of DIO. Male Sprague-Dawley rats were fed a low- or high-fat diet (HFD:40%digestible energy from lipids) for 10 weeks to elicit DIO (n=9). In a different cohort, rats were fed a HFD for 15 weeks. After 9 weeks consuming a HFD, rats were injected daily for 6 weeks with 3 mg/kg AM251 (n=9) or saline via i.p. injection (n=9). After 10 weeks consuming a HFD, CB 1 and megalin protein expression were significantly increased in the kidneys of obese rats. Antagonism of CB 1 with AM251 significantly reduced weight gain, systolic blood pressure, plasma leptin, and reduced albuminuria and plasma creatinine levels in obese rats. Importantly, there was a significant reduction in tubular cross-section diameter in the obese rats treated with AM251. An improvement in albuminuria was likely due to the reduction in tubular size, reduced leptinaemia and maintenance of megalin expression levels. In obese rats, AM251 did not alter diastolic blood pressure, sodium excretion, creatinine clearance or expression of the fibrotic proteins VEGFA, TGFB1 and collagen IV in the kidney. This study demonstrates that treatment with CB 1 antagonist AM251 improves renal outcomes in obese rats.