Renal effects of chronic pharmacological manipulation of CB₂ receptors in rats with diet‐induced obesity

Abstract

BACKGROUND AND PURPOSEIn diabetic nephropathy agonism of CB2 receptors reduces albuminuria and podocyte loss; however, the role of CB 2 receptors in obesity-related nephropathy is unknown. The aim of this study was to determine the role of CB 2 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 APPROACHMale 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 RESULTSTen 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. CONCLUSIONSThis 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. AbbreviationsCB1 receptor, cannabinoid receptor 1; CB2 receptor, cannabinoid receptor 2; CKD, chronic kidney disease; DIO, diet-induced obesity; eGFR, estimated glomerular filtration rate; HFD, high-fat diet; PAS, periodic acid-Schiff

New insights into the yin and yang of the endocannabinoid system in health and disease

“…Aligning well with the above review, also within this issue is an original contribution from Jenkin et al (2016) that focuses on the role of CB 2 receptors in obesity-induced renal dysfunction. Using a high fat diet-induced rat model of obesity, they studied the effects of both activation (with AM1241) and blockade (with AM630) of the CB 2 receptor.…”

Selective Cannabinoid 2 Receptor Stimulation Reduces Tubular Epithelial Cell Damage after Renal Ischemia-Reperfusion Injury

“…The CB1 receptors are expressed in high abundance with a fairly broad localization pattern, which includes all segments of the nephron and vasculature (Hryciw and McAinch, 2016). On the other hand, the CB2 receptor has been primarily detected in the renal cortex, specifically in mesangial cells and podocytes in the glomerulus (Deutsch et al, 1997;Barutta et al, 2011), and in proximal tubular epithelial cells (Jenkin et al, 2010(Jenkin et al, , 2013(Jenkin et al, , 2016. The CB2 receptor is an attractive pharmaceutical target owing to the lack of psychotropic effects associated with CB1 receptor activation (Mukhopadhyay et al, 2010a).…”

Diet‐Induced Obesity in Cannabinoid‐2 Receptor Knockout Mice and Cannabinoid Receptor 1/2 Double‐Knockout Mice

“…Mice injected with the CB2R antagonist SR144528 for 4 weeks displayed a slight nonsignificant increase in body weight (24). In contrast, Jenkin et al reported that treatment with the CB2R agonist AM1241 or antagonist AM630 did not reduce weight gain or food consumption in diet-induced obese rodents (23). Using knockout models, Schmitz et al reported age-dependent proinflammatory obesity and visceral hypertrophy in CB2R-deficient mice on a standard diet compared with WT mice (26), a conclusion consistent with our findings of slightly higher body weight of CB2 −/− mice at baseline as well as after 12 weeks of LFD.…”