Protective Role of Cannabinoid Receptor Type 2 in a Mouse Model of Diabetic Nephropathy
- Federica Barutta1,
- Fabiana Piscitelli2,
- Silvia Pinach1,
- Graziella Bruno1,
- Roberto Gambino1,
- Maria Pia Rastaldi3,
- Gennaro Salvidio4,
- Vincenzo Di Marzo2,
- Paolo Cavallo Perin1 and
- Gabriella Gruden1⇓
- 1Diabetic Nephropathy Laboratory, Department of Internal Medicine, University of Turin, Turin, Italy
- 2Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR, Pozzuoli, Italy
- 3Renal Research Laboratory, Fondazione IRCCS, Ospedale Maggiore Policlinico and Fondazione D’Amico per la Ricerca sulle Malattie Renali, Milan, Italy
- 4Department of Cardionephrology, University of Genoa, Genoa, Italy
- Corresponding author: Gabriella Gruden, .
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-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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db10-1809/-/DC1.
- Received December 30, 2010.
- Accepted June 29, 2011.
- © 2011 by the American Diabetes Association.
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