Cannabinoid-2 receptor limits inflammation, oxidative/nitrosative stress, and cell death in nephropathy.
Cisplatin is an important chemotherapeutic agent; however, its nephrotoxicity limits its clinical use. Enhanced inflammatory response and oxidative/nitrosative stress seem to play a key role in the development of cisplatin-induced nephropathy. Activation of cannabinoid-2 (CB(2)) receptors with selective agonists exerts anti-inflammatory and tissue-protective effects in various disease models. We have investigated the role of CB(2) receptors in cisplatin-induced nephrotoxicity using the selective CB(2) receptor agonist HU-308 and CB(2) knockout mice. Cisplatin significantly increased inflammation (leukocyte infiltration, CXCL1/2, MCP-1, TNFalpha, and IL-1beta levels) and expression of adhesion molecule ICAM-1 and superoxide-generating enzymes NOX2, NOX4, and NOX1 and enhanced ROS generation, iNOS expression, nitrotyrosine formation, and apoptotic and poly(ADP-ribose) polymerase-dependent cell death in the kidneys of mice, associated with marked histopathological damage and impaired renal function (elevated serum BUN and creatinine levels) 3 days after the administration of the drug. CB(2) agonist attenuated the cisplatin-induced inflammatory response, oxidative/nitrosative stress, and cell death in the kidney and improved renal function, whereas CB(2) knockouts developed enhanced inflammation and tissue injury. Thus, the endocannabinoid system, through CB(2) receptors, protects against cisplatin-induced kidney damage by attenuating inflammation and oxidative/nitrosative stress, and selective CB(2) agonists may represent a promising novel approach to preventing this devastating complication of chemotherapy.
Mukhopadhyay
Partha
P
Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
Rajesh
Mohanraj
M
Pan
Hao
H
Patel
Vivek
V
Mukhopadhyay
Bani
B
Bátkai
Sándor
S
Gao
Bin
B
Haskó
György
G
Pacher
Pál
P
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D002186:Cannabinoids / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D007249:Inflammation; D007674:Kidney Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D007677:Kidney Function Tests; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D009195:Peroxidase / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000502:physiology*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D000970:Antineoplastic Agents; D002186:Cannabinoids; D017382:Reactive Oxygen Species; D043885:Receptor, Cannabinoid, CB2; C002744:3-nitrotyrosine; D014443:Tyrosine; C402416:HU 308; D009195:Peroxidase; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D002945:Cisplatin