J Pharmacol Exp Ther. 2017 Nov 29. pii: jpet.117.245522. doi: 10.1124/jpet.117.245522. [Epub ahead of print]
Selective cannabinoid 2 receptor stimulation reduces tubular epithelial cell damage following renal ischemia-reperfusion injury.
Pressly JD1, Mustafa SM1, Abidi A1, Alghamdi S1, Pandey P2, Roy KK2, Doerksen R2, Moore BM1, Park F3.
Author information
1university of Tennessee health science center.2University of Mississippi.3University of Tennessee Health Sciences Center fpark@uthsc.edu bmoore@uthsc.edu.
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. |
