PMID- 21810593 OWN - NLM STAT- MEDLINE DCOM- 20111031 LR - 20220331 IS - 1939-327X (Electronic) IS - 0012-1797 (Print) IS - 0012-1797 (Linking) VI - 60 IP - 9 DP - 2011 Sep TI - Protective role of cannabinoid receptor type 2 in a mouse model of diabetic nephropathy. PG - 2386-96 LID - 10.2337/db10-1809 [doi] AB - OBJECTIVE: The cannabinoid receptor type 2 (CB2) has protective effects in chronic degenerative diseases. Our aim was to assess the potential relevance of the CB2 receptor in both human and experimental diabetic nephropathy (DN). RESEARCH DESIGN AND METHODS: CB2 expression was studied in kidney biopsies from patients with advanced DN, in early experimental diabetes, and in cultured podocytes. Levels of endocannabinoids and related enzymes were measured in the renal cortex from diabetic mice. To assess the functional role of CB2, streptozotocin-induced diabetic mice were treated for 14 weeks with AM1241, a selective CB2 agonist. In these animals, we studied albuminuria, renal function, expression of podocyte proteins (nephrin and zonula occludens-1), and markers of both fibrosis (fibronectin and transforming growth factor-beta1) and inflammation (monocyte chemoattractant protein-1 [MCP-1], CC chemokine receptor 2 [CCR2], and monocyte markers). CB2 signaling was assessed in cultured podocytes. RESULTS: Podocytes express the CB2 receptor both in vitro and in vivo. CB2 was downregulated in kidney biopsies from patients with advanced DN, and renal levels of the CB2 ligand 2-arachidonoylglycerol were reduced in diabetic mice, suggesting impaired CB2 regulation. In experimental diabetes, AM1241 ameliorated albuminuria, podocyte protein downregulation, and glomerular monocyte infiltration, without affecting early markers of fibrosis. In addition, AM1241 reduced CCR2 expression in both renal cortex and cultured podocytes, suggesting that CB2 activation may interfere with the deleterious effects of MCP-1 signaling. CONCLUSIONS: The CB2 receptor is expressed by podocytes, and in experimental diabetes, CB2 activation ameliorates both albuminuria and podocyte protein loss, suggesting a protective effect of signaling through CB2 in DN. FAU - Barutta, Federica AU - Barutta F AD - Diabetic Nephropathy Laboratory, Department of Internal Medicine, University of Turin, Turin, Italy. FAU - Piscitelli, Fabiana AU - Piscitelli F FAU - Pinach, Silvia AU - Pinach S FAU - Bruno, Graziella AU - Bruno G FAU - Gambino, Roberto AU - Gambino R FAU - Rastaldi, Maria Pia AU - Rastaldi MP FAU - Salvidio, Gennaro AU - Salvidio G FAU - Di Marzo, Vincenzo AU - Di Marzo V FAU - Cavallo Perin, Paolo AU - Cavallo Perin P FAU - Gruden, Gabriella AU - Gruden G LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20110801 PL - United States TA - Diabetes JT - Diabetes JID - 0372763 RN - 0 (AM 1241) RN - 0 (Cannabinoids) RN - 0 (Chemokine CCL2) RN - 0 (Fibronectins) RN - 0 (Membrane Proteins) RN - 0 (Receptor, Cannabinoid, CB2) RN - 0 (Transforming Growth Factor beta1) RN - 0 (nephrin) SB - IM MH - Albuminuria/metabolism/physiopathology MH - Animals MH - Cannabinoids/pharmacology MH - Chemokine CCL2/metabolism MH - Diabetes Mellitus, Experimental/*metabolism/physiopathology MH - Diabetic Nephropathies/*metabolism/physiopathology MH - Disease Models, Animal MH - Fibronectins/metabolism MH - Humans MH - Kidney Cortex/drug effects/*metabolism/physiopathology MH - Membrane Proteins/metabolism MH - Mice MH - Podocytes/drug effects/*metabolism MH - Receptor, Cannabinoid, CB2/*metabolism MH - Transforming Growth Factor beta1/metabolism PMC - PMC3161308 EDAT- 2011/08/04 06:00 MHDA- 2011/11/01 06:00 PMCR- 2012/09/01 CRDT- 2011/08/04 06:00 PHST- 2011/08/04 06:00 [entrez] PHST- 2011/08/04 06:00 [pubmed] PHST- 2011/11/01 06:00 [medline] PHST- 2012/09/01 00:00 [pmc-release] AID - db10-1809 [pii] AID - 1809 [pii] AID - 10.2337/db10-1809 [doi] PST - ppublish SO - Diabetes. 2011 Sep;60(9):2386-96. doi: 10.2337/db10-1809. Epub 2011 Aug 1.