title: Chronic administration of AM251 improves albuminuria and renal tubular structure in obese rats.
abstract: Modulation of the endocannabinoid system as an anti-obesity therapeutic is well established; however, the direct effects of cannabinoid receptor 1 (CB1) antagonism on renal function and structure in a model of diet-induced obesity (DIO) are unknown. The aim of this study was to characterise the renal effects of the CB1 antagonist AM251 in a model of DIO. Male Sprague-Dawley rats were fed a low- or high-fat diet (HFD: 40% digestible energy from lipids) for 10 weeks to elicit DIO (n=9). In a different cohort, rats were fed a HFD for 15 weeks. After 9 weeks consuming a HFD, rats were injected daily for 6 weeks with 3 mg/kg AM251 (n=9) or saline via i.p. injection (n=9). After 10 weeks consuming a HFD, CB1 and megalin protein expression were significantly increased in the kidneys of obese rats. Antagonism of CB1 with AM251 significantly reduced weight gain, systolic blood pressure, plasma leptin, and reduced albuminuria and plasma creatinine levels in obese rats. Importantly, there was a significant reduction in tubular cross-section diameter in the obese rats treated with AM251. An improvement in albuminuria was likely due to the reduction in tubular size, reduced leptinaemia and maintenance of megalin expression levels. In obese rats, AM251 did not alter diastolic blood pressure, sodium excretion, creatinine clearance or expression of the fibrotic proteins VEGFA, TGFB1 and collagen IV in the kidney. This study demonstrates that treatment with CB1 antagonist AM251 improves renal outcomes in obese rats.
authors: College of Health and Biomedicine Centre for Chronic Disease Prevention and Management, Victoria University, St Albans Campus, PO Box 14428, Melbourne, Victoria 8001, Australia The Florey Institute of Neuroscience and Mental Health Parkville, Melbourne, Victoria 3052, Australia Department of Physiology The University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia.
authors: Kayte A
authors: KA
authors: Jenkin
authors: College of Health and Biomedicine Centre for Chronic Disease Prevention and Management, Victoria University, St Albans Campus, PO Box 14428, Melbourne, Victoria 8001, Australia The Florey Institute of Neuroscience and Mental Health Parkville, Melbourne, Victoria 3052, Australia Department of Physiology The University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia.
authors: Lannie
authors: L
authors: O'Keefe
authors: College of Health and Biomedicine Centre for Chronic Disease Prevention and Management, Victoria University, St Albans Campus, PO Box 14428, Melbourne, Victoria 8001, Australia The Florey Institute of Neuroscience and Mental Health Parkville, Melbourne, Victoria 3052, Australia Department of Physiology The University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia.
authors: Anna C
authors: AC
authors: Simcocks
authors: College of Health and Biomedicine Centre for Chronic Disease Prevention and Management, Victoria University, St Albans Campus, PO Box 14428, Melbourne, Victoria 8001, Australia The Florey Institute of Neuroscience and Mental Health Parkville, Melbourne, Victoria 3052, Australia Department of Physiology The University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia.
authors: Esther
authors: E
authors: Grinfeld
authors: College of Health and Biomedicine Centre for Chronic Disease Prevention and Management, Victoria University, St Albans Campus, PO Box 14428, Melbourne, Victoria 8001, Australia The Florey Institute of Neuroscience and Mental Health Parkville, Melbourne, Victoria 3052, Australia Department of Physiology The University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia College of Health and Biomedicine Centre for Chronic Disease Prevention and Management, Victoria University, St Albans Campus, PO Box 14428, Melbourne, Victoria 8001, Australia The Florey Institute of Neuroscience and Mental Health Parkville, Melbourne, Victoria 3052, Australia Department of Physiology The University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia.
authors: Michael L
authors: ML
authors: Mathai
authors: College of Health and Biomedicine Centre for Chronic Disease Prevention and Management, Victoria University, St Albans Campus, PO Box 14428, Melbourne, Victoria 8001, Australia The Florey Institute of Neuroscience and Mental Health Parkville, Melbourne, Victoria 3052, Australia Department of Physiology The University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia.
authors: Andrew J
authors: AJ
authors: McAinch
authors: College of Health and Biomedicine Centre for Chronic Disease Prevention and Management, Victoria University, St Albans Campus, PO Box 14428, Melbourne, Victoria 8001, Australia The Florey Institute of Neuroscience and Mental Health Parkville, Melbourne, Victoria 3052, Australia Department of Physiology The University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia Deanne.Skelly@unimelb.edu.au.
authors: Deanne H
authors: DH
authors: Hryciw
mesh_terms: D000419:Albuminuria / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D006801:Humans; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009765:Obesity / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010880:Piperidines / Q000008:administration & dosage*; D011720:Pyrazoles / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; C103505:AM 251; D003094:Collagen
keywords: cannabinoids; kidney; leptin; obesity