Abstract
BackgroundHemorrhagic 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.MethodsRats 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.ResultsHemorrhagic 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).ConclusionHemorrhagic 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.
Highlights
Hemorrhagic shock is associated with increased mortality and organ failure [1]
Due to its key function in the regulation of endothelial barrier function, targeting Tie2 has been proposed as a promising strategy to improve outcome of critically ill patients [12]. In line with this hypothesis, we previously reported that targeting Tie2 with vasculotide, a Tie2 agonist, restored cremaster perfusion and reduced microvascular leakage in a rat model of hemorrhagic shock and fluid resuscitation [10]
Fluid resuscitation targeted a mean arterial pressure (MAP) > 50 mmHg (p < 0.0001) and increased heart rate (p < 0.01 vs. 1 h Hemorrhagic shock (HS)), both values did not restore to baseline values (p < 0.0001 R + 0.5 h vs. baseline)
Summary
Hemorrhagic shock is associated with increased mortality and organ failure [1]. Acute kidney injury (AKI) is a major complication following hemorrhagic shock and contributes to prolonged hospital stay and increased mortality [2]. Sublingual microcirculatory perfusion is disturbed immediately following hemorrhagic shock [1, 4] and prolonged disturbances in microcirculatory perfusion are associated with multiple organ failure [1]. Hemorrhagic shock is associated with acute kidney injury and increased mortality. Targeting the endothelial angiopoietin/Tie 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 Tie restores renal perfusion and function
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