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 elevated rates of mortality. Therapies to treat AKI are currently not available, so identification of new targets that can be modulated to ameliorate renal damage upon diagnosis of AKI is essential. In this study, a novel cannabinoid receptor 2 (CB2) agonist, SMM-295 [3′-methyl-4-(2-(thiophen-2-yl)propan-2-yl)biphenyl-2,6-diol], was designed, synthesized, and tested in vitro and in silico. 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 human embryonic kidney 293 cells, SMM-295 was capable of reducing cAMP production with 66-fold selectivity for CB2 versus cannabinoid receptor 1 and dose-dependently increased mitogen-activated protein kinase and Akt phosphorylation. 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, where SMM-295 was immediately administered upon reperfusion of the kidneys after the ischemia episode. Histologic damage assessment 48 hours after reperfusion demonstrated reduced tubular damage in the presence of SMM-295. This was consistent with reduced plasma markers of renal dysfunction (i.e., creatinine and neutrophil gelatinase–associated lipocalin) in SMM-295–treated mice. Mechanistically, kidneys treated with SMM-295 were shown to have elevated activation of Akt with reduced terminal deoxynucleotidyl transferase–mediated digoxigenin-deoxyuridine nick-end labeling (TUNEL)–positive cells compared with vehicle-treated kidneys after IRI. These data suggest that selective CB2 receptor activation could be a potential therapeutic target in the treatment of AKI.
Footnotes
- Received October 4, 2017.
- Accepted November 22, 2017.
This work was partially funded by the University of Tennessee Health Science Center [institutional funds (to F.P.)], the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grants R01-DK090123 (to F.P.), and the National Institutes of Health National Institute of General Medical Sciences [Grants P20-GM104932 and R15-GM119061 (to R.J.D.)]. Supercomputer support from the National Science Foundation [Grant MRI1338056] and the Mississippi Center for Supercomputer Research [both to (R.J.D.)] is acknowledged. This investigation was conducted in part in a facility constructed with support from the National Institutes of Health Research Facilities Improvements Program [Grant C06-RR14503 (to R.J.D.)].
↵This article has supplemental material available at jpet.aspetjournals.org.
- Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics
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