title: Cannabinoid-2 receptor limits inflammation, oxidative/nitrosative stress, and cell death in nephropathy.
abstract: 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.
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Partha
authors.initials: P
authors.lastname: Mukhopadhyay
authors.forename: Mohanraj
authors.initials: M
authors.lastname: Rajesh
authors.forename: Hao
authors.initials: H
authors.lastname: Pan
authors.forename: Vivek
authors.initials: V
authors.lastname: Patel
authors.forename: Bani
authors.initials: B
authors.lastname: Mukhopadhyay
authors.forename: Sándor
authors.initials: S
authors.lastname: Bátkai
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.forename: György
authors.initials: G
authors.lastname: Haskó
authors.forename: Pál
authors.initials: P
authors.lastname: Pacher
mesh_terms: 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
chemical_list: 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