Selective cannabinoid 2 receptor stimulation reduces tubular epithelial cell damage after renal ischemia-reperfusion injury

Jeffrey D. Pressly, Suni M. Mustafa, Ammaar H. Adibi, Sahar Alghamdi, Pankaj Pandey, Kuldeep K. Roy, Robert J. Doerksen, Bob Moore, Frank Park

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI), which is an increasing problemin the clinic and has been associated with elevated rates of mortality. Therapies to treat AKI are currently not available, so identification of newtargets that can bemodulated to ameliorate renal damage upon diagnosis of AKI is essential. In this study, a novel cannabinoid receptor 2 (CB2) agonist, SMM-295 [39-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 mitogenactivated protein kinase and Akt phosphorylation. In vivo testing of the CB2 agonist was performed using a mouse model of bilateral IRI, which is a commonmodel tomimic 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-295were shown to have elevated activation of Akt with reduced terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nickend 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.

Original languageEnglish (US)
Pages (from-to)287-299
Number of pages13
JournalJournal of Pharmacology and Experimental Therapeutics
Volume364
Issue number2
DOIs
StatePublished - Feb 1 2018

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Cannabinoid Receptors
Reperfusion Injury
Acute Kidney Injury
Epithelial Cells
Kidney
Cannabinoid Receptor Agonists
Reperfusion
Digoxigenin
Deoxyuridine
DNA Nucleotidylexotransferase
Computer Simulation
Protein Kinases
Creatinine
Ischemia
Phosphorylation
Amino Acids
Mortality
Therapeutics

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Selective cannabinoid 2 receptor stimulation reduces tubular epithelial cell damage after renal ischemia-reperfusion injury. / Pressly, Jeffrey D.; Mustafa, Suni M.; Adibi, Ammaar H.; Alghamdi, Sahar; Pandey, Pankaj; Roy, Kuldeep K.; Doerksen, Robert J.; Moore, Bob; Park, Frank.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 364, No. 2, 01.02.2018, p. 287-299.

Research output: Contribution to journalArticle

Pressly, Jeffrey D. ; Mustafa, Suni M. ; Adibi, Ammaar H. ; Alghamdi, Sahar ; Pandey, Pankaj ; Roy, Kuldeep K. ; Doerksen, Robert J. ; Moore, Bob ; Park, Frank. / Selective cannabinoid 2 receptor stimulation reduces tubular epithelial cell damage after renal ischemia-reperfusion injury. In: Journal of Pharmacology and Experimental Therapeutics. 2018 ; Vol. 364, No. 2. pp. 287-299.
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