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 (CB 2), 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 CB 2 agonists in type 2 diabetes. In this study, we investigated the effects of a CB 2 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. BTBR ob/ob mice received, from 10 to 21 weeks of age, vehicle, the selective CB 2 agonist HU910, or lisinopril used as standard therapy for comparison. BTBR wild-type mice served as controls. Treatment with CB 2 agonist reduced progressive albuminuria of BTBR ob/ob mice to a similar extent as ACE inhibitor. The antiproteinuric effect of CB 2 agonist was associated with the amelioration of the defective nephrin expression in podocytes of diabetic mice. CB 2 agonist limited mesangial matrix expansion, fibronectin accumulation and sclerosis. Glomerular infiltration of Mac-2-positive monocytes/machrophages was attenuated by CB 2 agonist, at least in part due to the drug's ability to reduce MCP-1 chemotactic signals. Renoprotective effects of CB 2 were similar to those achieved by ACE inhibitor. These results suggest that CB 2 agonism is a potential option to be added to the available therapeutic armamentarium for type 2 diabetic nephropathy.