Blockade of cannabinoid CB1 receptors improves renal function, metabolic profile, and increased survival of obese Zucker rats.
Obesity is a major risk factor in the development of chronic renal failure. Rimonabant, a cannabinoid CB1 receptor antagonist, improves body weight and metabolic disorders; however, its effect on mortality and chronic renal failure associated with obesity is unknown. Obese Zucker rats received either rimonabant or vehicle for 12 months and were compared to a pair-fed but untreated group of obese rats. Mortality in the obese rats was significantly reduced by rimonabant along with a sustained decrease in body weight, transient reduction in food intake, and an increase in plasma adiponectin. This was associated with significant reduction in plasma total cholesterol, low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio, triglycerides, glucose, norepinephrine, plasminogen activator inhibitor 1, and preservation of pancreatic weight and beta-cell mass index. The cannabinoid antagonist attenuated the increase in proteinuria, urinary N-acetylglucosaminidase excretion, plasma creatinine, and urea nitrogen levels while improving creatinine clearance. Renal hypertrophy along with glomerular and tubulointerstitial lesions were reduced by rimonabant. Although the drug did not modify hemodynamics, it normalized the pressor response to angiotensin II. Our study suggests that in a rat model of chronic renal failure due to obesity, rimonabant preserves renal function and increases survival.
Janiak
P
P
Cardiovascular Therapeutic Department, Sanofi-Aventis Research & Development, Chilly-Mazarin, France. philip.janiak@sanofi-aventis.com
Poirier
B
B
Bidouard
J-P
JP
Cadrouvele
C
C
Pierre
F
F
Gouraud
L
L
Barbosa
I
I
Dedio
J
J
Maffrand
J-P
JP
Le Fur
G
G
O'Connor
S
S
Herbert
J-M
JM
D052242:Adiponectin / Q000097:blood; D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects / Q000502:physiology; D007668:Kidney / Q000187:drug effects / Q000502:physiology*; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000517:prevention & control; D008055:Lipids / Q000097:blood; D008297:Male; D009765:Obesity / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011924:Rats, Zucker; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000502:physiology; D000077285:Rimonabant; D016019:Survival Analysis
D052242:Adiponectin; D008055:Lipids; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant