title: Protective role of cannabinoid receptor type 2 in a mouse model of diabetic nephropathy.
abstract: 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).
  
  
  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-β1) 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.
authors.affiliation: Diabetic Nephropathy Laboratory, Department of Internal Medicine, University of Turin, Turin, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Barutta
authors.forename: Fabiana
authors.initials: F
authors.lastname: Piscitelli
authors.forename: Silvia
authors.initials: S
authors.lastname: Pinach
authors.forename: Graziella
authors.initials: G
authors.lastname: Bruno
authors.forename: Roberto
authors.initials: R
authors.lastname: Gambino
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Rastaldi
authors.forename: Gennaro
authors.initials: G
authors.lastname: Salvidio
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.forename: Paolo
authors.initials: P
authors.lastname: Cavallo Perin
authors.forename: Gabriella
authors.initials: G
authors.lastname: Gruden
mesh_terms: D000419:Albuminuria / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D002186:Cannabinoids / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: C439263:AM 1241; D002186:Cannabinoids; D018932:Chemokine CCL2; D005353:Fibronectins; D008565:Membrane Proteins; D043885:Receptor, Cannabinoid, CB2; D053773:Transforming Growth Factor beta1; C113267:nephrin