Dexmedetomidine protects against renal ischemia and reperfusion injury by inhibiting the JAK/STAT signaling activation

Abstract

BackgroundThe α2-adrenoreceptor agonist dexmedetomidine is known to provide renoprotection against ischemia and reperfusion (I/R) injury. However the underlying molecular mechanisms remain unclear. The purpose of this study was to investigate whether the Janus kinase and signal transducer and activator of transcription (JAK/STAT) signaling pathway plays a role in dexmedetomidine’s renoprotection.MethodsI/R model was induced by bilateral renal pedicle clamping for 45 min followed by 48 h of reperfusion in male Wistar rat. Sham laparotomy served as controls. Animals received dexmedetomidine (50 μg/kg, i.p.) in the absence or presence of atipamezole (250 μg/kg, i.p.), or vehicle (DMSO) in the absence or presence of selective JAK2 inhibitor tyrphostin AG490 (10 mg/kg, i.p.) before ischemia. Renal function, histology, apoptosis, expression of cleaved caspase 3 protein, intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1) and phosphorylations of JAK2, STAT1 and STAT3 were assessed.ResultsThe animals treated with either dexmedetomidine or AG490 exhibited an improved renal functional recovery, attenuated histological lesions and reduced number of apoptotic tubular epithelial cells. Either dexmedetomidine or AG490 inhibited the phosphorylations of JAK2 and its downstream molecule STAT1 and STAT3, accompanied by down-regulation the expression of cleaved caspase 3, ICAM-1 and MCP-1 proteins, and significantly ameliorated renal I/R injury.ConclusionsDexmedetomidine protects kidney against I/R injury, at least in part, through its inhibitory effects on injury-induced activation of JAK/STAT signaling pathway. If our data can be extrapolated to clinical setting, then dexmedetomidine may therefore serve as a clinical strategy to treat/prevent perioperative renal I/R injury.

The effect of dexmedetomidine against oxidative and tubular damage induced by renal ischemia reperfusion in rats

“…In another study, it has been observed that the dex application reduces kidney caspase 3, plasma ICAM-1 and monocyte chemo attractant protein-1 (MCP-1) levels; and these effects have been inhibited by atipamezole, which is a-2 antagonist. 19 These results suggest that the dex causes these effects through a-2 adrenergic receptors.…”

Acute hyperglycemia prevents dexmedetomidine-induced preconditioning against renal ischemia-reperfusion injury

“…Recent studies have showed that dexmedetomidine could reduce the renal I/R injury, by inhibiting Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway 4 or activating cell survival signal p-AKT 5 . Koca et al 14 showed that dexmedetomidine also attenuated sepsis-induced kidney injury and apoptosis in the rat model of sepsis.…”

“…The dose (50 μg/kg, i.p.) referred to previous literature in rats 4,14 . Whether the larger dose of dexmedetomidine decreases renal I/R injury under hyperglycemia may need to be elucidated in further research.…”

“…Thus, approaches to lessen I/R injury have been extensively studied, and administration of pharmacologic agents such as anesthetics have been shown to be protective against renal I/R injury 2,3 . Dexmedetomidine, a commonly used anesthetic, could exert renoprotective effects on normoglycemic animals when administered before renal I/R [4][5][6] .…”

The future of marginal kidney repair in the context of normothermic machine perfusion

“…The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway plays a critical role in cytokine production mediating IRI 19. Dexmedetomidine, an α2‐adrenoreceptor agonist, inhibits the phosphorylation of JAK/STAT proteins, and has proved to be an effective agent in slowing the progression of renal IRI in rodents 20. Upstream of the JAK/STAT pathway lies nuclear factor kappa B (NF‐κB), a transcription factor that has also been shown to regulate the inflammatory cascade in IRI.…”