Cannabinoid-2 receptor limits inflammation, oxidative/nitrosative stress, and cell death in nephropathy

• Published in: Free radical biology & medicine Vol. 48; no. 3; pp. 457 - 467
• Main Authors: Mukhopadhyay, Partha, Rajesh, Mohanraj, Pan, Hao, Patel, Vivek, Mukhopadhyay, Bani, Bátkai, Sándor, Gao, Bin, Haskó, György, Pacher, Pál
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-02-2010
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis - physiology; Cannabinoid receptors; Cannabinoids - pharmacology; Caspases - metabolism; Cisplatin - pharmacology; Free radicals; In Situ Nick-End Labeling; Inflammation; Kidney Diseases - immunology; Kidney Diseases - metabolism; Kidney Diseases - pathology; Kidney Function Tests; Lipid Peroxidation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nephropathy; Nitrosative stress; Oxidation-Reduction; Oxidative Stress; Peroxidase - metabolism; Poly(ADP-ribose) Polymerases - metabolism; Reactive Oxygen Species - metabolism; Receptor, Cannabinoid, CB2 - physiology; Tyrosine - analogs & derivatives; Tyrosine - metabolism; Oxidative stress; MCP-1; Free radicals; HU-308; NT; PARP; CXCL1/KC/N51; Inflammation; MPO; Nitrosative stress; CB 2; ICAM-1/CD54; Nephropathy; ROS; CXCL2/MIP-2; iNOS; Cannabinoid receptors
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2009.11.022

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, TNFα, and IL-1β 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.