title: Dual therapy targeting the endocannabinoid system prevents experimental diabetic nephropathy.
abstract: BACKGROUND
  The endocannabinoid system has been implicated in the pathogenesis of diabetic nephropathy (DN). We investigated the effect of combined therapy with AM6545, a 'peripherally' restricted cannabinoid receptor type 1 (CB1R) neutral antagonist, and AM1241, a cannabinoid receptor type 2 (CB2R) agonist, in experimental DN.
  
  
  METHODS
  Renal function and structure, podocyte proteins and markers of both fibrosis and inflammation were studied in streptozotocin-induced diabetic mice treated for 14 weeks with vehicle, AM6545, AM1241 and AM6545-AM1241.
  
  
  RESULTS
  Single treatment with either AM6545 or AM1241 alone reduced diabetes-induced albuminuria and prevented nephrin loss both in vivo and in vitro in podocytes exposed to glycated albumin. Dual therapy performed better than monotherapies, as it abolished albuminuria, inflammation, tubular injury and markedly reduced renal fibrosis. Converging anti-inflammatory mechanisms provide an explanation for this greater efficacy as dual therapy abolished diabetes-induced renal monocyte infiltration and M1/M2 macrophage imbalance in vivo and abrogated the profibrotic effect of M1 macrophage-conditioned media on cultured mesangial cells.
  
  
  CONCLUSIONS
  'Peripheral' CB1R blockade is beneficial in experimental DN and this effect is synergically magnified by CB2R activation.
authors.affiliation: Department of Medical Sciences, University of Turin, Torino, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Barutta
authors.affiliation: Department of Medical Sciences, University of Turin, Torino, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Grimaldi
authors.affiliation: Department of Medical Sciences, University of Turin, Torino, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Gambino
authors.affiliation: Center for Drug Discovery, Northeastern University, Boston, MA, USA.
authors.forename: Kiran
authors.initials: K
authors.lastname: Vemuri
authors.affiliation: Center for Drug Discovery, Northeastern University, Boston, MA, USA.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
authors.affiliation: Department of Medical Sciences, University of Turin, Torino, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Annaratone
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry - CNR, Pozzuoli, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: di Marzo
authors.affiliation: Department of Medical Sciences, University of Turin, Torino, Italy.
authors.forename: Graziella
authors.initials: G
authors.lastname: Bruno
authors.affiliation: Department of Medical Sciences, University of Turin, Torino, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Gruden
mesh_terms: D000419:Albuminuria / Q000517:prevention & control; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D063386:Cannabinoid Receptor Agonists / Q000008:administration & dosage*; D063387:Cannabinoid Receptor Antagonists / Q000008:administration & dosage*; D002186:Cannabinoids / Q000008:administration & dosage; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy*; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000008:administration & dosage*; D018375:Neutrophil Activation / Q000187:drug effects; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage*
chemical_list: C439263:AM 1241; C551825:AM6545; D000893:Anti-Inflammatory Agents; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D002186:Cannabinoids; D004338:Drug Combinations; D009025:Morpholines; D011720:Pyrazoles
keywords: CB1R antagonist; CB2R agonist; albuminuria; diabetic nephropathy; endocannabinoid system