Dual Inhibition of Cannabinoid-1 Receptor and iNOS Attenuates Obesity-induced Chronic Kidney Disease.

Obesity, an important risk factor for developing chronic kidney disease (CKD), affects the kidneys by two main molecular signaling pathways: the endocannabinoid/CB₁ R system, whose activation in obesity promotes renal inflammation, fibrosis, and injury; and the inducible nitric oxide synthase (iNOS), which generates reactive oxygen species resulting in oxidative stress. Hence, a combined peripheral inhibitory molecule that targets both CB₁ R and iNOS may serve as an efficacious therapeutic agent against obesity-induced CKD.

Here, we describe the effect of a novel peripherally restricted, orally bioavailable dual CB₁ R/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 R antagonist (JD5037; 3 mg kg^-1 ), iNOS antagonist (1400W; 10 mg kg^-1 ), and pair feeding. High-fat diet-induced obese mice were treated orally with these compounds or vehicle (Veh) for 28 days. Standard diet fed mice treated with Veh served as controls.

Enhanced expression of CB₁ R 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 R. An additional interesting finding is that these beneficial effects on the kidney were partially associated with modulating renal adiponectin signaling.

Collectively, our results highlight the therapeutic relevance of blocking CB₁ R and iNOS in ameliorating obesity-induced CKD.