Dexmedetomidine Preconditioning Protects Rats from Renal Ischemia–Reperfusion Injury Accompanied with Biphasic Changes of Nuclear Factor-Kappa B Signaling

Abstract

Acute kidney injury (AKI) is one of the most common and troublesome perioperative complications. Dexmedetomidine (DEX) is a potent α2-adrenoceptor (α2-AR) agonist with anti-inflammatory and renoprotective effects. In this study, a rat renal ischemia–reperfusion injury (IRI) model was induced. At 24 h after reperfusion, the IRI-induced damage and the renoprotection of DEX preconditioning were confirmed both biochemically and histologically. Changes in nuclear factor-kappa B (NF-κB), as well as its downstream anti-inflammatory factor A20 and proinflammatory factor tumor necrosis factor-α (TNF-α), were detected. Atipamezole, a nonselective antagonist, was then added 5 min before the administration of DEX to further analyze DEX’s effects on NF-κB, and another anti-inflammatory medicine, methylprednisolone, was used in comparison with DEX, to further analyze DEX’s effects on NF-κB. Different concentrations of DEX (0 nM, 0.1 nM, 1 nM, 10 nM, 100 nM, 1 μM, and 10 μM) were applied to preincubated human renal tubular epithelial cell line (HK-2) cells in vitro. After anoxia and reoxygenation, the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium assay and enzyme-linked immunosorbent assay (ELISA) were performed to evaluate the levels of NF-κB downstream anti-inflammatory cytokines. The results showed that, unlike methylprednisolone, DEX preconditioning led to a time-dependent biphasic change (first activation then inhibition) of NF-κB in the rat renal IRI models that were given 25 μg/kg i.p. It was accompanied by a similarly biphasic change of TNF-α and an early and persistent upregulation of A20. In vitro, DEX’s cellular protection showed a concentration-dependent biphasic change which was protective within the range of 0 to 100 nM but became opposite when concentrations are greater than 1 μM. The changes in the A20 and NF-κB messenger RNA (mRNA) levels were consistent with the renoprotective ability of DEX. In other words, DEX preconditioning protected the rats from renal IRI via regulation biphasic change of NF-κB signaling.

Carnosine alleviates diabetic nephropathy by targeting GNMT, a key enzyme mediating renal inflammation and fibrosis

“…Interestingly, we first found that GNMT was down-regulated observably in the serum of DN patients. GNMT is an enzyme dependent on S-adenosine l-methionine (SAM) that catalyzes the conversion of glycine to creatine (27)(28)(29). SAM dependent methyltransferases are inhibited by S-adenosyl-L-homocysteine (SAH), and GNMT is believed to play a key role in other methyl transfer reactions as a regulator of the cell SAM/SAH ratio (30,31).…”

Organ-Protective Effects and the Underlying Mechanism of Dexmedetomidine

“…DEX has shown its anti-inflammatory and antiapoptotic effects in multiple animal models [46][47][48][49][50][51]. As we mentioned above, the anti-inflammatory effect of DEX is achieved by inhibiting the TLR4/NF-κB [47], JAK2-STAT3 [25,50], and NF-κB/COX-2 pathways [27,52]; activating the ERK1/2 pathway [53]; and releasing acetylcholine (ACh) through antisympathetic effects via the cholinergic pathway [13]. At the same time, DEX also reduces neuronal apoptosis through a variety of mechanisms that enhance the viability of the neurocyte.…”

Intranasal Dexmedetomidine May be a Worthy Alternative for Sedation in Preterm Infants: A Retrospective Single Center Study

“…This effect may be significant in perinatal ischemic-hypoxic encephalopathy, necrotizing enterocolitis, PVL and bronchopulmonary dysplasia, which are beyond the scope of our study [37][38][39]. Extensive research in animal models has shown protective effects of dexmedetomidine in additional systems including the heart, the kidneys, the liver, and more [40][41][42].…”