Hemorrhagic shock is associated with acute kidney injury and increased mortality. Targeting the endothelial angiopoietin/Tie2 system, which regulates endothelial permeability, previously reduced hemorrhagic shock-induced vascular leakage. We hypothesized that as a consequence of vascular leakage, renal perfusion and function is impaired and that activating Tie2 restores renal perfusion and function. Rats underwent 1 h of hemorrhagic shock and were treated with either vasculotide or PBS as control, followed by fluid resuscitation for 4 h. Microcirculatory perfusion was measured in the renal cortex and cremaster muscle using contrast echography and intravital microscopy, respectively. Changes in the angiopoietin/Tie2 system and renal injury markers were measured in plasma and on protein and mRNA level in renal tissue. Renal edema formation was determined by wet/dry weight ratios and renal structure by histological analysis. Hemorrhagic shock significantly decreased renal perfusion (240 ± 138 to 51 ± 40, p < 0.0001) and cremaster perfusion (12 ± 2 to 5 ± 2 perfused vessels, p < 0.0001) compared to baseline values. Fluid resuscitation partially restored both perfusion parameters, but both remained below baseline values (renal perfusion 120 ± 58, p = 0.08, cremaster perfusion 7 ± 2 perfused vessels, p < 0.0001 compared to baseline). Hemorrhagic shock increased circulating angiopoietin-1 (p < 0.0001), angiopoietin-2 (p < 0.0001) and soluble Tie2 (p = 0.05), of which angiopoietin-2 elevation was associated with renal edema formation (r = 0.81, p < 0.0001). Hemorrhagic shock induced renal injury, as assessed by increased levels of plasma neutrophil gelatinase-associated lipocalin (NGAL: p < 0.05), kidney injury marker-1 (KIM-1; p < 0.01) and creatinine (p < 0.05). Vasculotide did not improve renal perfusion (p > 0.9 at all time points) or reduce renal injury (NGAL p = 0.26, KIM-1 p = 0.78, creatinine p > 0.9, renal edema p = 0.08), but temporarily improved cremaster perfusion at 3 h following start of fluid resuscitation compared to untreated rats (resuscitation + 3 h: 11 ± 3 vs 8 ± 3 perfused vessels, p < 0.05). Hemorrhagic shock-induced renal impairment cannot be restored by standard fluid resuscitation, nor by activation of Tie2. Future treatment strategies should focus on reducing angiopoietin-2 levels or on activating Tie2 via an alternative strategy.

中文翻译：

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靶向Tie2对失血性休克大鼠肾灌注障碍的影响

失血性休克与急性肾损伤和死亡率增加有关。靶向调节血管通透性的内皮血管生成素/ Tie2系统，以前减少了失血性休克引起的血管渗漏。我们假设由于血管渗漏，肾灌注和功能受损，激活Tie2恢复肾灌注和功能。大鼠进行了1小时的失血性休克，并以血管肽或PBS作为对照进行了治疗，然后进行了液体复苏4 h。分别使用对比声像图和活体显微镜对肾皮质和提睾肌中的微循环灌注进行测量。在血浆中以及在肾组织中的蛋白和mRNA水平上测量了血管生成素/ Tie2系统和肾损伤标记物的变化。肾水肿的形成通过干重比和组织学分析确定肾结构。与基线值相比，出血性休克显着降低了肾脏灌注（240±138至51±40，p <0.0001）和cremaster灌注（12±2至5±2灌注血管，p <0.0001）。液体复苏可部分恢复两个灌注参数，但均保持在基线值以下（肾脏灌注120±58，p = 0.08，cremaster灌注7±2个灌注血管，与基线相比p <0.0001）。失血性休克增加循环血管生成素1（p <0.0001），血管生成素2（p <0.0001）和可溶性Tie2（p = 0.05），其中血管生成素2升高与肾水肿形成有关（r = 0.81，p <0.0001） ）。失血性休克引起的肾损伤，如通过血浆中性粒细胞明胶酶相关脂质运载蛋白（NGAL：p <0.05），肾损伤标志物1（KIM-1; p <0.01）和肌酐（p <0.05）升高的水平进行评估。血管舒缩肽不能改善肾脏灌注（在所有时间点上p> 0.9）或减轻肾脏损伤（NGAL p = 0.26，KIM-1 p = 0.78，肌酐p> 0.9，肾水肿p = 0.08），但暂时改善了cremaster灌注与未治疗的大鼠相比，开始液体复苏后3小时（复苏+ 3小时：11±3 vs 8±3灌注血管，p <0.05）。不能通过标准的液体复苏或通过激活Tie2来恢复失血性休克引起的肾功能损害。未来的治疗策略应侧重于降低血管生成素2水平或通过替代策略激活Tie2。肾损伤标志物1（KIM-1； p <0.01）和肌酐（p <0.05）。血管舒缩肽不能改善肾脏灌注（在所有时间点上p> 0.9）或减轻肾脏损伤（NGAL p = 0.26，KIM-1 p = 0.78，肌酐p> 0.9，肾水肿p = 0.08），但暂时改善了cremaster灌注与未治疗的大鼠相比，开始液体复苏后3小时（复苏+ 3小时：11±3 vs 8±3灌注血管，p <0.05）。不能通过标准的液体复苏或通过激活Tie2来恢复失血性休克引起的肾功能损害。未来的治疗策略应侧重于降低血管生成素2水平或通过替代策略激活Tie2。肾损伤标志物1（KIM-1； p <0.01）和肌酐（p <0.05）。血管舒缩肽不能改善肾脏灌注（在所有时间点上p> 0.9）或减轻肾脏损伤（NGAL p = 0.26，KIM-1 p = 0.78，肌酐p> 0.9，肾水肿p = 0.08），但暂时改善了cremaster灌注与未治疗的大鼠相比，开始液体复苏后3小时（复苏+ 3小时：11±3 vs 8±3灌注血管，p <0.05）。不能通过标准的液体复苏或通过激活Tie2来恢复失血性休克引起的肾功能损害。未来的治疗策略应侧重于降低血管生成素2水平或通过替代策略激活Tie2。26，KIM-1 p = 0.78，肌酐p> 0.9，肾水肿p = 0.08），但与未治疗的大鼠相比，在液体复苏开始后3 h临时改善了cremaster灌注（复苏+ 3 h：11±3 vs 8± 3个灌注血管，p <0.05）。不能通过标准的液体复苏或通过激活Tie2来恢复失血性休克引起的肾功能损害。未来的治疗策略应侧重于降低血管生成素2水平或通过替代策略激活Tie2。26，KIM-1 p = 0.78，肌酐p> 0.9，肾水肿p = 0.08），但与未治疗的大鼠相比，在液体复苏开始后3 h临时改善了cremaster灌注（复苏+ 3 h：11±3 vs 8± 3个灌注血管，p <0.05）。不能通过标准的液体复苏或通过激活Tie2来恢复失血性休克引起的肾功能损害。未来的治疗策略应侧重于降低血管生成素2水平或通过替代策略激活Tie2。也不通过激活Tie2。未来的治疗策略应侧重于降低血管生成素2水平或通过替代策略激活Tie2。也不通过激活Tie2。未来的治疗策略应侧重于降低血管生成素2水平或通过替代策略激活Tie2。