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

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/CB₁ 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 CB₁ 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 CB₁ 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 CB₁ receptor antagonist (JD5037; 3 mg·kg⁻¹), iNOS antagonist (1400W; 10 mg·kg⁻¹), and pair feeding. Mice with high-fat 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 CB₁ 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 CB₁ 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 CB₁ receptors and iNOS in ameliorating obesity-induced CKD.