K A Jenkin1, L O'Keefe1, A C Simcocks1, J F Briffa2, M L Mathai1,3, A J McAinch1, D H Hryciw2. 1. Centre for Chronic Disease Prevention and Management, College of Health and Biomedicine, Victoria University, St Albans Campus, Melbourne, Vic., Australia. 2. Department of Physiology, University of Melbourne, Melbourne, Vic., Australia. 3. The Florey Institute of Neuroscience and Mental Health, Melbourne, Vic., Australia.
Abstract
BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY 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. LINKED ARTICLES: 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.
BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY 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 obeserats, it leads to improvements in obesity-related renal dysfunction. LINKED ARTICLES: 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: L Hanus; A Breuer; S Tchilibon; S Shiloah; D Goldenberg; M Horowitz; R G Pertwee; R A Ross; R Mechoulam; E Fride Journal: Proc Natl Acad Sci U S A Date: 1999-12-07 Impact factor: 11.205
Authors: K A Jenkin; L O'Keefe; A C Simcocks; J F Briffa; M L Mathai; A J McAinch; D H Hryciw Journal: Br J Pharmacol Date: 2015-02-27 Impact factor: 8.739
Authors: Jeffrey D Pressly; Suni M Mustafa; Ammaar H Adibi; Sahar Alghamdi; Pankaj Pandey; Kuldeep K Roy; Robert J Doerksen; Bob M Moore; Frank Park Journal: J Pharmacol Exp Ther Date: 2017-11-29 Impact factor: 4.030
Authors: K A Jenkin; L O'Keefe; A C Simcocks; J F Briffa; M L Mathai; A J McAinch; D H Hryciw Journal: Br J Pharmacol Date: 2015-02-27 Impact factor: 8.739
Authors: Julie H Ishida; Reto Auer; Eric Vittinghoff; Mark J Pletcher; Jared P Reis; Stephen Sidney; Kirsten L Johansen; Kirsten Bibbins-Domingo; Carmen A Peralta; Michael G Shlipak Journal: Clin J Am Soc Nephrol Date: 2017-08-24 Impact factor: 10.614