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.
Highlights
The α2-adrenoreceptor agonist dexmedetomidine is known to provide renoprotection against ischemia and reperfusion (I/R) injury
We found that AG490 down-regulated its downstream molecules, STAT1 and STAT3, but this was associated with improved renal function and attenuated histological lesions against renal I/R injury
Our results indicated that dexmedetomidine’s renoprotective effect was at least partially dependent on inhibiting the activation of Tyrosine kinases (JAKs)/transcription factors (STATs) signaling pathway induced by renal I/R, which may contribute to ameliorating renal injury
Summary
The α2-adrenoreceptor agonist dexmedetomidine is known to provide renoprotection against ischemia and reperfusion (I/R) injury. Despite advances in preventive strategies and supportive measures, AKI is still associated with prolonged hospitalization as well as high morbidity and mortality rates which have not decreased significantly over the Dexmedetomidine (DEX) is among a number of prophylactic and therapeutic measures that have been used to reduce perioperative AKI [6,7]. It is a highly selective α2-adrenoreceptor agonist with sedative, analgesic, sympatholytic and hemodynamic stabilizing properties [8]. The underlying molecular mechanisms of dexmedetomidine’s renoprotection remain unknown
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