The effect of targeting Tie2 on hemorrhagic shock-induced renal perfusion disturbances in rats

Intensive Care Medicine Experimental

Esther de Groot¹  Anoek L. I. van Leeuwen²  Nicole A. M. Dekker²  Charissa E. van den Brom³  Marc G. Vervloet⁴  Matijs van Meurs⁵  Joris J. T. H. Roelofs⁶  Paul Van Slyke⁷ 

[1] Department of Anesthesiology, Experimental Laboratory for Vital Signs, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands;Department of Anesthesiology, Experimental Laboratory for Vital Signs, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands;Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherlands;Department of Cardiothoracic Surgery, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherlands;Department of Anesthesiology, Experimental Laboratory for Vital Signs, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands;Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherlands;Department of Intensive Care, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands;Department of Nephrology, Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, the Netherlands;Department of Pathology and Medical Biology, Medical Biology Section, University Medical Center Groningen, Groningen, The Netherlands;Department of Critical Care Medicine, University Medical Center Groningen, Groningen, The Netherlands;Department of Pathology, Amsterdam Cardiovascular Sciences, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands;Vasomune Therapeutics, Toronto, Canada;

关键词: Hemorrhage;    Acute kidney injury;    Contrast-enhanced ultrasonography;    Microcirculatory perfusion;    Vascular leakage;    Endothelium;   

DOI  :  10.1186/s40635-021-00389-5

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY