Dual inhibition of cannabinoid CB₁ receptor and inducible NOS attenuates obesity‐induced chronic kidney disease

Abstract

Background and Purpose: Obesity, an important risk factor for developing chronic kidney disease (CKD), affects the kidneys by two main molecular signalling pathways: the endocannabinoid/CB 1 receptor system, whose activation in obesity promotes renal inflammation, fibrosis, and injury, and the inducible NOS (iNOS), which generates ROS resulting in oxidative stress. Hence, a compound that inhibits both peripheral CB 1 receptors and iNOS may serve as an effective therapeutic agent against obesity-induced CKD.Experimental Approach: Here, we describe the effect of a novel peripherally restricted, orally bioavailable dual CB 1 receptor/iNOS antagonist, MRI-1867(3 mg·kg −1 ), in ameliorating obesity-induced CKD, and compared its metabolic and renal efficacies to a stand-alone peripheral CB 1 receptor antagonist (JD5037; 3 mg·kg −1 ), iNOS antagonist (1400W; 10 mg·kg −1 ), and pair feeding. Mice with highfat diet-induced obesity were treated orally with these compounds or vehicle (Veh) for 28 days. Standard diet-fed mice treated with Veh served as controls.Key Results: Enhanced expression of CB 1 receptors and iNOS in renal tubules was found in human kidney patients with obesity and other CKDs. The hybrid inhibitor ameliorated obesity-induced kidney morphological and functional changes via decreasing kidney inflammation, fibrosis, oxidative stress, and renal injury. Some of these features were independent of the improved metabolic profile mediated via inhibition of CB 1 receptors. An additional interesting finding is that these beneficial effects on the kidney were partially associated with modulating renal adiponectin signalling.Conclusions and Implications: Collectively, our results highlight the therapeutic relevance of blocking CB 1 receptors and iNOS in ameliorating obesity-induced CKD.---

Caloric restriction, physical exercise, and CB1 receptor blockade as an efficient combined strategy for bodyweight control and cardiometabolic status improvement in male rats

“…Pharmacological treatment with specific CB1 receptor antagonist has been described to improve renal structure and functionality in experimental models of chronic kidney disease 47 . Moreover, a recent study by Udi et al 48 describes the administration of a novel peripherally restricted, orally bioavailable dual CB1 receptor/iNOS antagonist on a preclinical model of obesity-induced chronic kidney disease. The hybrid inhibitor ameliorated obesity-induced kidney morphological and functional changes via decreasing kidney inflammation, fibrosis, oxidative stress, and renal injury.…”

Caloric Restriction, Physical Exercise, and CB1 Receptor Blockade as an Efficient Combined Strategy for Bodyweight Control and Cardiometabolic Status Improvement.

“…The consumption of HFD in our study caused a marked increase in their renal clearance rate, a measure of glomerular filtration, associated with albuminuria, a well-known marker of renal damage, both being reversed by the weight-loss and maintenance interventions of caloric restriction and physical exercise to values similar to SD group. Pharmacological treatment with specific CB1 receptor antagonist has been described to improve renal structure and functionality in experimental models of chronic kidney disease 36,37 .…”

Targeting the Endocannabinoid CB1 Receptor to Treat Body Weight Disorders: A Preclinical and Clinical Review of the Therapeutic Potential of Past and Present CB1 Drugs

“…JD5037 displays low brain penetrance, yet high selectivity for the CB1 receptor, and has previously been shown to reduce body weight and appetite by re-establishing leptin sensitivity [ 67 , 169 ]. JD5037 administration to DIO mice over a 28 day period caused an approximate 20% decrease in body weight compared to vehicle [ 68 ]. A toxicity study examined JD5037 administration in rats and dogs.…”

“…The decreased food intake following the acute administration of ENP11 is comparable to AM251, and more pronounced than that of rimonabant. MRI-1867 is a low brain penetrating CB1 inverse agonist developed for the treatment of liver fibrosis, and DIO mice treated with MRI-1867 for 28 days experienced significant reductions in body weight and food intake, and increased energy expenditure [ 68 , 170 ]. Other similar compounds include Compound 6a, BMS-725519, BMS-811064, and BMS-812204 [ 73 , 171 ].…”