Cargando…
The effect of targeting Tie2 on hemorrhagic shock-induced renal perfusion disturbances in rats
BACKGROUND: 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...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126531/ https://www.ncbi.nlm.nih.gov/pubmed/33997943 http://dx.doi.org/10.1186/s40635-021-00389-5 |
_version_ | 1783693779495026688 |
---|---|
author | van Leeuwen, Anoek L. I. Dekker, Nicole A. M. Van Slyke, Paul de Groot, Esther Vervloet, Marc G. Roelofs, Joris J. T. H. van Meurs, Matijs van den Brom, Charissa E. |
author_facet | van Leeuwen, Anoek L. I. Dekker, Nicole A. M. Van Slyke, Paul de Groot, Esther Vervloet, Marc G. Roelofs, Joris J. T. H. van Meurs, Matijs van den Brom, Charissa E. |
author_sort | van Leeuwen, Anoek L. I. |
collection | PubMed |
description | BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40635-021-00389-5. |
format | Online Article Text |
id | pubmed-8126531 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-81265312021-05-18 The effect of targeting Tie2 on hemorrhagic shock-induced renal perfusion disturbances in rats van Leeuwen, Anoek L. I. Dekker, Nicole A. M. Van Slyke, Paul de Groot, Esther Vervloet, Marc G. Roelofs, Joris J. T. H. van Meurs, Matijs van den Brom, Charissa E. Intensive Care Med Exp Research Articles BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40635-021-00389-5. Springer International Publishing 2021-05-17 /pmc/articles/PMC8126531/ /pubmed/33997943 http://dx.doi.org/10.1186/s40635-021-00389-5 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Articles van Leeuwen, Anoek L. I. Dekker, Nicole A. M. Van Slyke, Paul de Groot, Esther Vervloet, Marc G. Roelofs, Joris J. T. H. van Meurs, Matijs van den Brom, Charissa E. The effect of targeting Tie2 on hemorrhagic shock-induced renal perfusion disturbances in rats |
title | The effect of targeting Tie2 on hemorrhagic shock-induced renal perfusion disturbances in rats |
title_full | The effect of targeting Tie2 on hemorrhagic shock-induced renal perfusion disturbances in rats |
title_fullStr | The effect of targeting Tie2 on hemorrhagic shock-induced renal perfusion disturbances in rats |
title_full_unstemmed | The effect of targeting Tie2 on hemorrhagic shock-induced renal perfusion disturbances in rats |
title_short | The effect of targeting Tie2 on hemorrhagic shock-induced renal perfusion disturbances in rats |
title_sort | effect of targeting tie2 on hemorrhagic shock-induced renal perfusion disturbances in rats |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126531/ https://www.ncbi.nlm.nih.gov/pubmed/33997943 http://dx.doi.org/10.1186/s40635-021-00389-5 |
work_keys_str_mv | AT vanleeuwenanoekli theeffectoftargetingtie2onhemorrhagicshockinducedrenalperfusiondisturbancesinrats AT dekkernicoleam theeffectoftargetingtie2onhemorrhagicshockinducedrenalperfusiondisturbancesinrats AT vanslykepaul theeffectoftargetingtie2onhemorrhagicshockinducedrenalperfusiondisturbancesinrats AT degrootesther theeffectoftargetingtie2onhemorrhagicshockinducedrenalperfusiondisturbancesinrats AT vervloetmarcg theeffectoftargetingtie2onhemorrhagicshockinducedrenalperfusiondisturbancesinrats AT roelofsjorisjth theeffectoftargetingtie2onhemorrhagicshockinducedrenalperfusiondisturbancesinrats AT vanmeursmatijs theeffectoftargetingtie2onhemorrhagicshockinducedrenalperfusiondisturbancesinrats AT vandenbromcharissae theeffectoftargetingtie2onhemorrhagicshockinducedrenalperfusiondisturbancesinrats AT vanleeuwenanoekli effectoftargetingtie2onhemorrhagicshockinducedrenalperfusiondisturbancesinrats AT dekkernicoleam effectoftargetingtie2onhemorrhagicshockinducedrenalperfusiondisturbancesinrats AT vanslykepaul effectoftargetingtie2onhemorrhagicshockinducedrenalperfusiondisturbancesinrats AT degrootesther effectoftargetingtie2onhemorrhagicshockinducedrenalperfusiondisturbancesinrats AT vervloetmarcg effectoftargetingtie2onhemorrhagicshockinducedrenalperfusiondisturbancesinrats AT roelofsjorisjth effectoftargetingtie2onhemorrhagicshockinducedrenalperfusiondisturbancesinrats AT vanmeursmatijs effectoftargetingtie2onhemorrhagicshockinducedrenalperfusiondisturbancesinrats AT vandenbromcharissae effectoftargetingtie2onhemorrhagicshockinducedrenalperfusiondisturbancesinrats |