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Thirty-Eight-Negative Kinase 1 Is a Mediator of Acute Kidney Injury in Experimental and Clinical Traumatic Hemorrhagic Shock
Trauma represents a major socioeconomic burden worldwide. After a severe injury, hemorrhagic shock (HS) as a frequent concomitant aspect is a central driver of systemic inflammation and organ damage. The kidney is often strongly affected by traumatic-HS, and acute kidney injury (AKI) poses the patie...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479097/ https://www.ncbi.nlm.nih.gov/pubmed/32983160 http://dx.doi.org/10.3389/fimmu.2020.02081 |
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author | Halbgebauer, Rebecca Karasu, Ebru Braun, Christian K. Palmer, Annette Braumüller, Sonja Schultze, Anke Schäfer, Fabian Bückle, Sarah Eigner, Alica Wachter, Ulrich Radermacher, Peter Resuello, Ranillo R. G. Tuplano, Joel V. Nilsson Ekdahl, Kristina Nilsson, Bo Armacki, Milena Kleger, Alexander Seufferlein, Thomas Kalbitz, Miriam Gebhard, Florian Lambris, John D. van Griensven, Martijn Huber-Lang, Markus |
author_facet | Halbgebauer, Rebecca Karasu, Ebru Braun, Christian K. Palmer, Annette Braumüller, Sonja Schultze, Anke Schäfer, Fabian Bückle, Sarah Eigner, Alica Wachter, Ulrich Radermacher, Peter Resuello, Ranillo R. G. Tuplano, Joel V. Nilsson Ekdahl, Kristina Nilsson, Bo Armacki, Milena Kleger, Alexander Seufferlein, Thomas Kalbitz, Miriam Gebhard, Florian Lambris, John D. van Griensven, Martijn Huber-Lang, Markus |
author_sort | Halbgebauer, Rebecca |
collection | PubMed |
description | Trauma represents a major socioeconomic burden worldwide. After a severe injury, hemorrhagic shock (HS) as a frequent concomitant aspect is a central driver of systemic inflammation and organ damage. The kidney is often strongly affected by traumatic-HS, and acute kidney injury (AKI) poses the patient at great risk for adverse outcome. Recently, thirty-eight-negative kinase 1 (TNK1) was proposed to play a detrimental role in organ damage after trauma/HS. Therefore, we aimed to assess the role of TNK1 in HS-induced kidney injury in a murine and a post hoc analysis of a non-human primate model of HS comparable to the clinical situation. Mice and non-human primates underwent resuscitated HS at 30 mmHg for 60 min. 5 h after the induction of shock, animals were assessed for systemic inflammation and TNK1 expression in the kidney. In vitro, murine distal convoluted tubule cells were stimulated with inflammatory mediators to gain mechanistic insights into the role of TNK1 in kidney dysfunction. In a translational approach, we investigated blood drawn from either healthy volunteers or severely injured patients at different time points after trauma (from arrival at the emergency room and at fixed time intervals until 10 days post injury; identifier: NCT02682550, https://clinicaltrials.gov/ct2/show/NCT02682550). A pronounced inflammatory response, as seen by increased IL-6 plasma levels as well as early signs of AKI, were observed in mice, non-human primates, and humans after trauma/HS. TNK1 was found in the plasma early after trauma-HS in trauma patients. Renal TNK1 expression was significantly increased in mice and non-human primates after HS, and these effects with concomitant induction of apoptosis were blocked by therapeutic inhibition of complement C3 activation in non-human primates. Mechanistically, in vitro data suggested that IL-6 rather than C3 cleavage products induced upregulation of TNK1 and impaired barrier function in renal epithelial cells. In conclusion, these data indicate that C3 inhibition in vivo may inhibit an excessive inflammatory response and mediator release, thereby indirectly neutralizing TNK1 as a potent driver of organ damage. In future studies, we will address the therapeutic potential of direct TNK1 inhibition in the context of severe tissue trauma with different degrees of additional HS. |
format | Online Article Text |
id | pubmed-7479097 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-74790972020-09-26 Thirty-Eight-Negative Kinase 1 Is a Mediator of Acute Kidney Injury in Experimental and Clinical Traumatic Hemorrhagic Shock Halbgebauer, Rebecca Karasu, Ebru Braun, Christian K. Palmer, Annette Braumüller, Sonja Schultze, Anke Schäfer, Fabian Bückle, Sarah Eigner, Alica Wachter, Ulrich Radermacher, Peter Resuello, Ranillo R. G. Tuplano, Joel V. Nilsson Ekdahl, Kristina Nilsson, Bo Armacki, Milena Kleger, Alexander Seufferlein, Thomas Kalbitz, Miriam Gebhard, Florian Lambris, John D. van Griensven, Martijn Huber-Lang, Markus Front Immunol Immunology Trauma represents a major socioeconomic burden worldwide. After a severe injury, hemorrhagic shock (HS) as a frequent concomitant aspect is a central driver of systemic inflammation and organ damage. The kidney is often strongly affected by traumatic-HS, and acute kidney injury (AKI) poses the patient at great risk for adverse outcome. Recently, thirty-eight-negative kinase 1 (TNK1) was proposed to play a detrimental role in organ damage after trauma/HS. Therefore, we aimed to assess the role of TNK1 in HS-induced kidney injury in a murine and a post hoc analysis of a non-human primate model of HS comparable to the clinical situation. Mice and non-human primates underwent resuscitated HS at 30 mmHg for 60 min. 5 h after the induction of shock, animals were assessed for systemic inflammation and TNK1 expression in the kidney. In vitro, murine distal convoluted tubule cells were stimulated with inflammatory mediators to gain mechanistic insights into the role of TNK1 in kidney dysfunction. In a translational approach, we investigated blood drawn from either healthy volunteers or severely injured patients at different time points after trauma (from arrival at the emergency room and at fixed time intervals until 10 days post injury; identifier: NCT02682550, https://clinicaltrials.gov/ct2/show/NCT02682550). A pronounced inflammatory response, as seen by increased IL-6 plasma levels as well as early signs of AKI, were observed in mice, non-human primates, and humans after trauma/HS. TNK1 was found in the plasma early after trauma-HS in trauma patients. Renal TNK1 expression was significantly increased in mice and non-human primates after HS, and these effects with concomitant induction of apoptosis were blocked by therapeutic inhibition of complement C3 activation in non-human primates. Mechanistically, in vitro data suggested that IL-6 rather than C3 cleavage products induced upregulation of TNK1 and impaired barrier function in renal epithelial cells. In conclusion, these data indicate that C3 inhibition in vivo may inhibit an excessive inflammatory response and mediator release, thereby indirectly neutralizing TNK1 as a potent driver of organ damage. In future studies, we will address the therapeutic potential of direct TNK1 inhibition in the context of severe tissue trauma with different degrees of additional HS. Frontiers Media S.A. 2020-08-26 /pmc/articles/PMC7479097/ /pubmed/32983160 http://dx.doi.org/10.3389/fimmu.2020.02081 Text en Copyright © 2020 Halbgebauer, Karasu, Braun, Palmer, Braumüller, Schultze, Schäfer, Bückle, Eigner, Wachter, Radermacher, Resuello, Tuplano, Nilsson Ekdahl, Nilsson, Armacki, Kleger, Seufferlein, Kalbitz, Gebhard, Lambris, van Griensven and Huber-Lang. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Halbgebauer, Rebecca Karasu, Ebru Braun, Christian K. Palmer, Annette Braumüller, Sonja Schultze, Anke Schäfer, Fabian Bückle, Sarah Eigner, Alica Wachter, Ulrich Radermacher, Peter Resuello, Ranillo R. G. Tuplano, Joel V. Nilsson Ekdahl, Kristina Nilsson, Bo Armacki, Milena Kleger, Alexander Seufferlein, Thomas Kalbitz, Miriam Gebhard, Florian Lambris, John D. van Griensven, Martijn Huber-Lang, Markus Thirty-Eight-Negative Kinase 1 Is a Mediator of Acute Kidney Injury in Experimental and Clinical Traumatic Hemorrhagic Shock |
title | Thirty-Eight-Negative Kinase 1 Is a Mediator of Acute Kidney Injury in Experimental and Clinical Traumatic Hemorrhagic Shock |
title_full | Thirty-Eight-Negative Kinase 1 Is a Mediator of Acute Kidney Injury in Experimental and Clinical Traumatic Hemorrhagic Shock |
title_fullStr | Thirty-Eight-Negative Kinase 1 Is a Mediator of Acute Kidney Injury in Experimental and Clinical Traumatic Hemorrhagic Shock |
title_full_unstemmed | Thirty-Eight-Negative Kinase 1 Is a Mediator of Acute Kidney Injury in Experimental and Clinical Traumatic Hemorrhagic Shock |
title_short | Thirty-Eight-Negative Kinase 1 Is a Mediator of Acute Kidney Injury in Experimental and Clinical Traumatic Hemorrhagic Shock |
title_sort | thirty-eight-negative kinase 1 is a mediator of acute kidney injury in experimental and clinical traumatic hemorrhagic shock |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479097/ https://www.ncbi.nlm.nih.gov/pubmed/32983160 http://dx.doi.org/10.3389/fimmu.2020.02081 |
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