Selective Cannabinoid 2 Receptor Stimulation Reduces Tubular Epithelial Cell Damage after Renal Ischemia-Reperfusion Injury

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.

Structure-Based Identification of Potent Natural Product Chemotypes as Cannabinoid Receptor 1 Inverse Agonists

“…The CB2 docking was done only for those molecules that were not selective in the CB1 and CB2 radioligand-binding assay. The CB2 receptor grid was prepared by choosing the centroid of residues Lys109 3.28 , Ser112 3.31 , Phe117 3.36 , Trp194 5.43 , Trp258 6.48 , Lys278, and Ser285 7.39 as reported in our previous publication [ 29 ], and the docking was carried out with the same protocol as for the CB1 model. In the XP docking, no constraint was applied for CB2 receptor docking.…”

“…This approach is being used by several researchers who have shown that peripherally restricted CB1 antagonists and inverse agonists reduce body weight and improve metabolic profile in vivo, while being devoid of CNS-mediated side effects [ 23 , 24 ]. On the other hand, the CB2 receptor is also an important target for the discovery of therapeutics for neuro-inflammation, cardiometabolic disorder, cardiac ischemia, renal ischemia–reperfusion injury, and other diseases/disorders [ 25 , 26 , 27 , 28 , 29 ].…”

Preprotection of Tea Polysaccharides with Different Molecular Weights Can Reduce the Adhesion between Renal Epithelial Cells and Nano-Calcium Oxalate Crystals

“…In the pathological state, excessive free radicals produced in the body cause oxidative damage to kidney tissues, leading to the formation of diseases, such as kidney stones [22]. TPSs have good antioxidant capacity, and TPS treatment can improve the ability of renal epithelial cells to resist oxidative damage [23,24]. The results showed that TPSs protected HK-2 cells from damage caused by nano-COM crystals by reducing ROS production.…”

Sıçan İnce Barsak İskemi/Reperfüzyon Hasarında İleum ve Akciğer Dokusunda Görülen Damar Dışına Protein Kaçışının, Kanabinoid 2 Reseptör Agonisti (Am-1241) ile Kontrolü

“…İ/R çalışmasında akciğer dokusundaki miyeloperoksidaz aktivasyonu, şam kontrol grubu ile İ/R grubu arasında karşılaştırma yapılması sonucu akciğer dokusunda evans miktarının kontrol grubuna göre daha fazla olduğu bulunmuştur. Aynı zamanda CB2 agonisti ile karaciğer dokusunda ve diğer dokularda İ/R hasarına karşı koruyucu özelliğe sahip olduğu bilimsel çalışmalar sonucu bulunmuştur (19)(20)(21). Astım sonucu solunum yollarında meydana gelen bozulmanın önemli bir etkisi akciğer dokusunda plazma proteinlerinin kılcal damardan sızmasıdır.…”

“…Kanabidiol, bağışıklık sisteminde etkili olan TNFα ve nitrik oksit derecesini önemli ölçüde düzenlemiştir (23). Kanabinoidlerin yapısal özelliklerinden dolayı doku hasarına karşı koruyucu ilaç gibi kullanılabilir (20,22).…”