Therapy with a Selective Cannabinoid Receptor Type 2 Agonist Limits Albuminuria and Renal Injury in Mice with Type 2 Diabetic Nephropathy

Background/Aims: A critical involvement of the endocannabinoid/cannabinoid receptor system in diabetes and its complications has been recognized. Experimental evidence suggested that activation of the cannabinoid receptor type 2 (CB₂), which is expressed in the kidney by podocytes and inflammatory cells, had a protective role in early streptozotocin-induced type 1 diabetes in mice. No experimental evidence is so far available on the effects of CB₂ agonists in type 2 diabetes. In this study, we investigated the effects of a CB₂ agonist given at a phase of overt disease on renal functional and structural changes in BTBR ob/ob mice, a model of type 2 diabetic nephropathy. Methods: BTBR ob/ob mice received, from 10 to 21 weeks of age, vehicle, the selective CB₂ agonist HU910, or lisinopril used as standard therapy for comparison. BTBR wild-type mice served as controls. Results: Treatment with CB₂ agonist reduced progressive albuminuria of BTBR ob/ob mice to a similar extent as ACE inhibitor. The antiproteinuric effect of CB₂ agonist was associated with the amelioration of the defective nephrin expression in podocytes of diabetic mice. CB₂ agonist limited mesangial matrix expansion, fibronectin accumulation and sclerosis. Glomerular infiltration of Mac-2-positive monocytes/machrophages was attenuated by CB₂ agonist, at least in part due to the drug's ability to reduce MCP-1 chemotactic signals. Renoprotective effects of CB₂ were similar to those achieved by ACE inhibitor. Conclusion: These results suggest that CB₂ agonism is a potential option to be added to the available therapeutic armamentarium for type 2 diabetic nephropathy.