Role of mTOR signaling pathway in dexmedetomidine-induced reduction of renal ischemia-reperfusion injury in rats: the relationship with HIF-1α

Abstract

Objective To evaluate the role of mammalian target of rapamycin (mTOR) signaling pathway in dexmedetomidine-induced reduction of renal ischemia-reperfusion (I/R) injury in rats and the relationship with hypoxia-inducible factor 1 (HIF-1α). Methods Seventy-two male Sprague-Dawley rats, aged 10–12 weeks, weighing 220–260 g, were randomly divided into 4 groups (n=18 each) using a random number table: sham operation group (group S), group I/R, dexmedetomidine group (group Dex), and rapamicyn + dexmedetomidine group (group Rpm+ Dex). Renal I/R was produced by occlusion of bilateral renal pedicles for 35 min follow by reperfusion in anesthetized rats in I/R, Dex and Rpm+ Dex groups.Bilateral renal pedicles were only exposed, and then the abdominal cavity was closed in group S. Dexdetomidine 50 μg/kg was injected intraperitoneally at 30 min before I/R in group Dex.In group Rpm+ Dex, rapamicyn 1.5 mg/kg and dexdetomidine 50 μg/kg were injected intraperitoneally, and renal I/R model was established 30 min later.Immediately after onset of reperfusion, and at 4 and 24 h of reperfusion (T1-3), blood samples were collected from the caudal vein for measurement of serum creatinine and blood urea nitrogen (BUN) concentrations.After blood sampling at T1-3, the rats were sacrificed, and the renal specimens were obtained for detection of HIF-1α, erythropoietin (EPO) and mTOR expression by Western blot.Their kidneys were removed at T3, and cut into sections which were stained with haematoxylin and eosin and examined under microscope.Acute renal tubular necrosis was scored.The cell apoptosis in renal tissues was detected by TUNEL assay, and apoptosis index (AI) was calculated. Results Compared with group S, the concentrations of serum creatinine and BUN, expression of HIF-1α, EPO and mTOR at T2, 3, AI at T3 and acute renal tubular necrosis score were significantly increased in the other three groups (P 0.05). Conclusion The mTOR signaling pathway is involved in dexmedetomidine-induced reduction of renal I/R injury, which may be related to dexmedetomidine-produced up-regulation of HIF-1α expression in renal tissues of rats. Key words: Sirolimus; Dexmedetomidine; Receptor-interacting protein serine-threonine kinases; Hypoxia-inducible factor 1, alpha subunit; Kidney; Reperfusion injury