Abstract
Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI), which is an increasing problem in the clinic and has been associated with increased rates of mortality. Currently, therapies to treat AKI are not available, so identification of new targets which, upon diagnosis of AKI, can be modulated to ameliorate renal damage is essential. In this study, a novel cannabinoid receptor 2 (CB2) agonist, SMM-295, was designed, synthesized, and tested in vitro and in silico. In vivo testing of the CB2 agonist was performed using a mouse model of bilateral IRI, which is a common model to mimic human AKI. Molecular docking of SMM-295 into a CB2 active-state homology model showed that SMM-295 interacts well with key amino acids to stabilize the active-state. In HEK-293 cells, SMM-295 was capable of reducing cAMP production with a 66-fold selectivity for the CB2 versus the cannabinoid receptor 1 (CB1), and dose-dependently increased MAPK and Akt phosphorylation. In mice, SMM-295 was immediately administered upon reperfusion of the kidneys following the ischemia episode. Histological damage assessment 48 hours after reperfusion demonstrated reduced tubular damage in the presence of SMM-295. This was consistent with the reduced plasma markers of renal dysfunction, i.e., creatinine and NGAL, in SMM-295 treated mice. Mechanistically, kidneys treated with SMM-295 were shown to have elevated activation of Akt with reduced TUNEL-positive cells compared to vehicle-treated kidney following IRI. These data suggests that selective CB2 receptor activation could be a potential therapeutic target in the treatment for AKI.
- cannabinoid receptors
- drug design
- g protein-coupled receptors (GPCRS)
- ischemia / reperfusion injury
- kidney
- The American Society for Pharmacology and Experimental Therapeutics