OPPOSING EFFECTS OF CB1 AND CB2 RECEPTORS ON INFLAMMATION, OXIDATIVE STRESS, AND CELL DEATH IN NEPROPATHY

Abstract

Cisplatin is an important chemotherapeutic agent; however, its nephrotoxicity limits its clinical use. Accumulating recent evidence suggests that cannabinoid 1 (CB1) receptor activation may promote inflammation/cell death and its pharmacological inhibition is associated with anti-inflammatory and tissue protective effects in various preclinical disease models. In contrast, accumulating evidence supports the anti-inflammatory role of Cannabinoid 2 (CB2) receptor activation in clinically relevant inflammatory disease models. Cisplatin-induced increased endocannabinoid content, activation of MAPK, cell death, enhanced inflammation and oxidative stress accompanied by marked histopathological damage and impaired renal function is attenuated by genetic deletion and pharmacological inhibition of CB1 receptors. These cisplatin-induced changes were attenuated by CB2 receptor agonist HU-308 while enhanced in CB2 receptor knockout mice collectively as well as the endocannabinoid system through CB1 receptors promotes the cisplatin-induced tissue injury by amplifying MAPK activation, cell death, inflammation and oxidative stress. In contrast, CB2 receptor activation appears to limit the injury. Thus CB1 inhibition or CB2 activation may exert beneficial effects in renal diseases associated with enhanced inflammation, oxidative stress and cell death.