CB1 cannabinoid receptors promote oxidative/nitrosative stress, inflammation and cell death in a murine nephropathy model.
OBJECTIVE
Accumulating recent evidence suggests that cannabinoid-1 (CB(1)) receptor activation may promote inflammation and cell death and its pharmacological inhibition is associated with anti-inflammatory and tissue-protective effects in various preclinical disease models, as well as in humans.


METHODS
In this study, using molecular biology and biochemistry methods, we have investigated the effects of genetic deletion or pharmacological inhibition of CB(1) receptors on inflammation, oxidative/nitrosative stress and cell death pathways associated with a clinically relevant model of nephropathy, induced by an important chemotherapeutic drug cisplatin.


RESULTS
Cisplatin significantly increased endocannabinoid anandamide content, activation of p38 and JNK mitogen-activated protein kinases (MAPKs), apoptotic and poly (ADP-ribose)polymerase-dependent cell death, enhanced inflammation (leucocyte infiltration, tumour necrosis factor-alpha and interleukin-1beta) and promoted oxidative/nitrosative stress [increased expressions of superoxide-generating enzymes (NOX2(gp91phox), NOX4), inducible nitric oxide synthase and tissue 4-hydroxynonenal and nitrotyrosine levels] in the kidneys of mice, accompanied by marked histopathological damage and impaired renal function (elevated creatinine and serum blood urea nitrogen) 3 days following its administration. Both genetic deletion and pharmacological inhibition of CB(1) receptors with AM281 or SR141716 markedly attenuated the cisplatin-induced renal dysfunction and interrelated oxidative/nitrosative stress, p38 and JNK MAPK activation, cell death and inflammatory response in the kidney.


CONCLUSIONS
The endocannabinoid system through CB(1) receptors promotes cisplatin-induced tissue injury by amplifying MAPK activation, cell death and interrelated inflammation and oxidative/nitrosative stress. These results also suggest that inhibition of CB(1) receptors may exert beneficial effects in renal (and most likely other) diseases associated with enhanced inflammation, oxidative/nitrosative stress and cell death.
Mukhopadhyay
Partha
P
Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892-9413, USA.
Pan
Hao
H
Rajesh
Mohanraj
M
Bátkai
Sándor
S
Patel
Vivek
V
Harvey-White
Judith
J
Mukhopadhyay
Bani
B
Haskó
György
G
Gao
Bin
B
Mackie
Ken
K
Pacher
Pál
P
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D016923:Cell Death / Q000235:genetics / Q000502:physiology*; D002945:Cisplatin; D004195:Disease Models, Animal; D063388:Endocannabinoids; D005989:Glycerides / Q000378:metabolism; D007249:Inflammation / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D009393:Nephritis / Q000139:chemically induced*; D018384:Oxidative Stress / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000077285:Rimonabant; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D009025:Morpholines; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C094503:glyceryl 2-arachidonate; D002945:Cisplatin; D000077285:Rimonabant; C109925:AM 281; C078814:anandamide