title: Renal effects of chronic pharmacological manipulation of CB2 receptors in rats with diet-induced obesity.
abstract: OBJECTIVE
  In diabetic nephropathy agonism of CB2 receptors reduces albuminuria and podocyte loss; however, the role of CB2 receptors in obesity-related nephropathy is unknown. The aim of this study was to determine the role of CB2 receptors in a model of diet-induced obesity (DIO) and characterize the hallmark signs of renal damage in response to agonism (AM1241) and antagonism (AM630) of CB2 receptors.
  
  
  METHODS
  Male Sprague Dawley rats were fed a high-fat diet (HFD: 40% digestible energy from lipids) for 10 weeks. In another cohort, after 9 weeks on a HFD, rats were injected daily with either 3 mg·kg(-1) AM1241, 0.3 mg·kg(-1) AM630 or saline for 6 weeks.
  
  
  RESULTS
  Ten weeks on a HFD significantly reduced renal expression of CB2 receptors and renal function. Treatment with AM1241 or AM630 did not reduce weight gain or food consumption in DIO. Despite this, AM1241 significantly reduced systolic BP, peri-renal adipose accumulation, plasma leptin, urinary protein, urinary albumin, urinary sodium excretion and the fibrotic markers TGF-β1, collagen IV and VEGF in kidney lysate. Treatment with AM630 of DIO rats significantly reduced creatinine clearance and increased glomerular area and kidney weight (gross and standardized for body weight). Diastolic BP, glucose tolerance, insulin sensitivity, plasma creatinine, plasma TGF-β1 and kidney expression of fibronectin and α-smooth muscle actin were not altered by either AM1241 or AM630 in DIO.
  
  
  CONCLUSIONS
  This study demonstrates that while agonism of CB2 receptors with AM1241 treatment for 6 weeks does not reduce weight gain in obese rats, it leads to improvements in obesity-related renal dysfunction.
  
  
  BACKGROUND
  This article is part of a themed section on Endocannabinoids. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.7/issuetoc.
authors.affiliation: Centre for Chronic Disease Prevention and Management, College of Health and Biomedicine, Victoria University, St Albans Campus, Melbourne, Vic., Australia.
authors.forename: K A
authors.initials: KA
authors.lastname: Jenkin
authors.affiliation: Centre for Chronic Disease Prevention and Management, College of Health and Biomedicine, Victoria University, St Albans Campus, Melbourne, Vic., Australia.
authors.forename: L
authors.initials: L
authors.lastname: O'Keefe
authors.affiliation: Centre for Chronic Disease Prevention and Management, College of Health and Biomedicine, Victoria University, St Albans Campus, Melbourne, Vic., Australia.
authors.forename: A C
authors.initials: AC
authors.lastname: Simcocks
authors.affiliation: Department of Physiology, University of Melbourne, Melbourne, Vic., Australia.
authors.forename: J F
authors.initials: JF
authors.lastname: Briffa
authors.affiliation: Centre for Chronic Disease Prevention and Management, College of Health and Biomedicine, Victoria University, St Albans Campus, Melbourne, Vic., Australia.|The Florey Institute of Neuroscience and Mental Health, Melbourne, Vic., Australia.
authors.forename: M L
authors.initials: ML
authors.lastname: Mathai
authors.affiliation: Centre for Chronic Disease Prevention and Management, College of Health and Biomedicine, Victoria University, St Albans Campus, Melbourne, Vic., Australia.
authors.forename: A J
authors.initials: AJ
authors.lastname: McAinch
authors.affiliation: Department of Physiology, University of Melbourne, Melbourne, Vic., Australia.
authors.forename: D H
authors.initials: DH
authors.lastname: Hryciw
mesh_terms: D000818:Animals; D002186:Cannabinoids / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage; D005355:Fibrosis; D007211:Indoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D008297:Male; D009765:Obesity / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015430:Weight Gain / Q000187:drug effects
chemical_list: C439263:AM 1241; D002186:Cannabinoids; D016207:Cytokines; D004041:Dietary Fats; D007211:Indoles; D043885:Receptor, Cannabinoid, CB2; C094023:iodopravadoline