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Potential amelioration of upregulated renal HIF-1alpha–endothelin-1 system by landiolol hydrochloride in a rat model of endotoxemia

机译:盐酸landiolol改善内毒素血症大鼠模型中肾脏HIF-1α-内皮素-1系统的潜在改善

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摘要

AimsEndothelin (ET)-1 is the best known potent vasoconstrictor and has been implicated in pathogenesis of sepsis-associated acute kidney injury (AKI) in human or lipopolysaccharide (LPS)-induced AKI in animal models. We have previously shown that ET-1 is highly up-regulated in renal tissues and in plasma after LPS administration. Here, we investigated whether landiolol hydrochloride, an ultra-short-acting beta-blocker, can play an important role in ameliorating levels of LPS-induced up-regulation of renal HIF-1α–ET-1 system and inflammatory cytokines in a rat model of endotoxemia.Main methodsMale Wistar rats at 8 weeks of age were either administered with: a) lipopolysaccharide (LPS) only for three hours (3 h) or b) LPS, followed by continuous administration of landiolol for 3 h; c) third group was only treated with vehicle.Key findingsAt 3 h after LPS administration there was: a) minimal injury in kidney tissues; b) circulatory levels of creatinine, blood urea nitrogen and NGAL increased and c) expression of inflammatory cytokines, such as TNF-α, IL-6 and iNOS increased at the level of both circulatory and renal tissues. In addition, LPS significantly induced renal expression of ET-1 and HIF-1α compared to control. Finally, treatment of LPS-administered rats with landiolol for 3 h normalized elevated serum markers of renal injury and up-regulated levels of renal HIF-1α–ET-1 system with normalization of TNF-α.SignificanceTaken together, these data led us to conclude that landiolol ameliorates the up-regulation of HIF-1α–ET-1 system in minimally morphologically-injured kidney and normalizes biomarkers of renal injury in early hours of endotoxemia of a rat model.
机译:AimsEndothelin(ET)-1是最知名的强效血管收缩药,已与动物模型中人类或脂多糖(LPS)诱导的AKI引起的败血症相关性急性肾损伤(AKI)的发病机理有关。先前我们已经证明,LPS给药后,ET-1在肾脏组织和血浆中高度上调。在这里,我们研究了盐酸兰地洛尔(一种超短效β受体阻滞剂)是否可以在减轻LPS诱导的大鼠肾脏HIF-1α–ET-1系统和炎症细胞因子上调水平中发挥重要作用主要方法对8周大的雄性Wistar大鼠进行以下两种给药:a)仅脂多糖(LPS)3小时(3 h)或b)LPS,然后连续给予landiolol 3 h。主要发现:LPS给药3小时后:a)肾脏组织损伤最小; b)肌酐,血液尿素氮和NGAL的循环水平增加,并且c)炎性细胞因子(如TNF-α,IL-6和iNOS)的表达在循环和肾脏组织水平均增加。另外,与对照相比,LPS显着诱导了ET-1和HIF-1α的肾脏表达。最后,使用兰地洛尔对LPS给药的大鼠进行3小时的治疗,可以使肾脏损伤的血清标志物升高,而使TNF-α的肾脏HIF-1α–ET-1系统水平上调。结论是,在动物内毒素血症的早期,landiolol改善了形态学损伤最小的肾脏中HIF-1α–ET-1系统的上调,并使肾脏损伤的生物标志物正常化。

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