Preconditioned suppression of prolyl-hydroxylases attenuates renal injury but increases mortality in septic murine models
Preconditioned suppression of prolyl-hydroxylases attenuates renal injury but increases mortality in septic murine models
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DOI：
10.1093/ndt/gfv442
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发表时间：
2016-07-01
影响因子：
6.1
通讯作者：
Wolf, Gunter
中科院分区：
文献类型：
--
作者：
Schindler, Katrin;Bondeva, Tzvetanka;Wolf, Gunter
败血症导致组织缺氧，可能导致多器官衰竭，包括急性肾损伤。低氧诱导的转录因子(HIF)调节细胞对低氧水平的适应。虽然HIFs在缺血/再灌注中的作用得到了更多的研究，但它们在脓毒症所致肾损伤中的作用还不是很清楚。本研究以12周龄C57BL6/J小鼠为模型，建立了盲肠结扎穿孔和腹膜污染及感染两种脓毒症模型，研究了抑制羟化酶(PhDS)激活HIF对感染性急性肾损伤的保护作用。通过在脓毒症前给予3，4-二羟基苯甲酸酯(3，4-DHB)实现对PHD的药理抑制，从而导致HIF激活。采用实时定量逆转录聚合酶链式反应、免疫组织化学和酶联免疫吸附试验分别检测基因表达、肾脏蛋白水平和肾功能参数。用高碘酸-席夫反应分析组织形态。通过肾损伤分子-1分析评估早期肾损伤。用末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法原位检测细胞凋亡。通过72小时的存活实验分析3，4-DHB对脓毒症的全身作用：与未治疗的脓毒症动物相比，在诱导脓毒症前给予HIFs的药理作用可减轻脓毒症相关的近端小管的空泡化和扩张，减少肾小管上皮细胞的凋亡，并与减少T细胞在肾组织中的浸润有关。PHD抑制可增加基础肾HIF-1α的表达和基础血浆HIF靶标促红细胞生成素和血管内皮生长因子的浓度。虽然它在两种模型中都保留了肾脏结构，但它以一种模型依赖的方式改善了肾功能。此外，在两种模型中，抑制PHD都会导致死亡率增加。肝功能分析显示，在脓毒症诱导前给予3，4-DHB会增加器官破坏，导致大量糖原丢失和肝细胞凋亡。综上所述，3，4-DHB对HIFs的药理激活虽然在脓毒症相关的肾脏损伤中显示出肾脏保护作用，但在脓毒症期间引起更严重的其他器官问题，如肝脏，导致死亡率增加。
Septic conditions contribute to tissue hypoxia, potentially leading to multiple organ failure, including acute kidney injury. The regulation of cellular adaptation to low oxygen levels is regulated by hypoxia-inducible transcription factors (HIFs). While the role of HIFs in ischaemia/reperfusion is more studied, their function in sepsis-induced renal injury is not well characterized. In this study, we investigated whether pharmacological activation of HIFs by suppression of prolyl-hydroxylases (PHDs) protects against septic acute kidney injury.Two models of sepsis-caecal ligation and punction and peritoneal contamination and infection-were induced on 12-week-old C57BL6/J mice. Pharmacological inhibition of PHDs, leading to HIF activation, was achieved by intraperitoneal application of 3,4-dihydroxybenzoate (3,4-DHB) before sepsis. A quantitative real-time reverse transcription polymerase chain reaction, immunohistology and enzyme-linked immunosorbent assays were utilized to detect gene expression, renal protein levels and renal functional parameters, respectively. Tissue morphology was analysed by periodic acid-Schiff reaction. Early kidney injury was estimated by kidney injury molecule-1 analyses. Apoptosis was detected in situ by terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling stain. The systemic effect of 3,4-DHB pretreatment in sepsis was analysed by 72-h survival studies.Pharmacological activation of HIFs before sepsis induction attenuated sepsis-related vacuolization and dilation of the proximal tubules, reduced tubular apoptosis and correlated to lower T-cell infiltration in renal tissue compared with the non-treated septic animals. PHD suppression elevated the basal renal HIF-1 alpha expression and basal plasma concentrations of HIF targets erythropoietin and vascular endothelial growth factor. Whereas it preserved renal structure in both models, it improved renal function in a model-dependent manner. Moreover, inhibition of PHDs led to increased mortality in both models. Analysis of liver function showed increased organ destruction with massive glycogen loss and hepatocyte's apoptosis due to 3,4-DHB administration before sepsis induction.In summary, the pharmacological activation of HIFs by 3,4-DHB administration, although it showed renoprotective effects in sepsis-related kidney injury, induced more severe problems in other organs such as the liver during sepsis, leading to increased mortality.