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Complement-mediated Damage to the Glycocalyx Plays a Role in Renal Ischemia-reperfusion Injury in Mice

BACKGROUND: Complement activation plays an important role in the pathogenesis of renal ischemia-reperfusion (IR) injury (IRI), but whether this involves damage to the vasculoprotective endothelial glycocalyx is not clear. We investigated the impact of complement activation on glycocalyx integrity an...

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Autores principales: Bongoni, Anjan K., Lu, Bo, McRae, Jennifer L., Salvaris, Evelyn J., Toonen, Erik J. M., Vikstrom, Ingela, Baz Morelli, Adriana, Pearse, Martin J., Cowan, Peter J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445655/
https://www.ncbi.nlm.nih.gov/pubmed/30993186
http://dx.doi.org/10.1097/TXD.0000000000000881
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author Bongoni, Anjan K.
Lu, Bo
McRae, Jennifer L.
Salvaris, Evelyn J.
Toonen, Erik J. M.
Vikstrom, Ingela
Baz Morelli, Adriana
Pearse, Martin J.
Cowan, Peter J.
author_facet Bongoni, Anjan K.
Lu, Bo
McRae, Jennifer L.
Salvaris, Evelyn J.
Toonen, Erik J. M.
Vikstrom, Ingela
Baz Morelli, Adriana
Pearse, Martin J.
Cowan, Peter J.
author_sort Bongoni, Anjan K.
collection PubMed
description BACKGROUND: Complement activation plays an important role in the pathogenesis of renal ischemia-reperfusion (IR) injury (IRI), but whether this involves damage to the vasculoprotective endothelial glycocalyx is not clear. We investigated the impact of complement activation on glycocalyx integrity and renal dysfunction in a mouse model of renal IRI. METHODS: Right nephrectomized male C57BL/6 mice were subjected to 22 minutes left renal ischemia and sacrificed 24 hours after reperfusion to analyze renal function, complement activation, glycocalyx damage, endothelial cell activation, inflammation, and infiltration of neutrophils and macrophages. RESULTS: Ischemia-reperfusion induced severe renal injury, manifested by significantly increased serum creatinine and urea, complement activation and deposition, loss of glycocalyx, endothelial activation, inflammation, and innate cell infiltration. Treatment with the anti-C5 antibody BB5.1 protected against IRI as indicated by significantly lower serum creatinine (P = 0.04) and urea (P = 0.003), tissue C3b/c and C9 deposition (both P = 0.004), plasma C3b (P = 0.001) and C5a (P = 0.006), endothelial vascular cell adhesion molecule-1 expression (P = 0.003), glycocalyx shedding (tissue heparan sulfate [P = 0.001], plasma syndecan-1 [P = 0.007], and hyaluronan [P = 0.02]), inflammation (high mobility group box-1 [P = 0.0003]), and tissue neutrophil (P = 0.0009) and macrophage (P = 0.004) infiltration. CONCLUSIONS: Together, our data confirm that the terminal pathway of complement activation plays a key role in renal IRI and demonstrate that the mechanism of injury involves shedding of the glycocalyx.
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spelling pubmed-64456552019-04-16 Complement-mediated Damage to the Glycocalyx Plays a Role in Renal Ischemia-reperfusion Injury in Mice Bongoni, Anjan K. Lu, Bo McRae, Jennifer L. Salvaris, Evelyn J. Toonen, Erik J. M. Vikstrom, Ingela Baz Morelli, Adriana Pearse, Martin J. Cowan, Peter J. Transplant Direct Basic Science BACKGROUND: Complement activation plays an important role in the pathogenesis of renal ischemia-reperfusion (IR) injury (IRI), but whether this involves damage to the vasculoprotective endothelial glycocalyx is not clear. We investigated the impact of complement activation on glycocalyx integrity and renal dysfunction in a mouse model of renal IRI. METHODS: Right nephrectomized male C57BL/6 mice were subjected to 22 minutes left renal ischemia and sacrificed 24 hours after reperfusion to analyze renal function, complement activation, glycocalyx damage, endothelial cell activation, inflammation, and infiltration of neutrophils and macrophages. RESULTS: Ischemia-reperfusion induced severe renal injury, manifested by significantly increased serum creatinine and urea, complement activation and deposition, loss of glycocalyx, endothelial activation, inflammation, and innate cell infiltration. Treatment with the anti-C5 antibody BB5.1 protected against IRI as indicated by significantly lower serum creatinine (P = 0.04) and urea (P = 0.003), tissue C3b/c and C9 deposition (both P = 0.004), plasma C3b (P = 0.001) and C5a (P = 0.006), endothelial vascular cell adhesion molecule-1 expression (P = 0.003), glycocalyx shedding (tissue heparan sulfate [P = 0.001], plasma syndecan-1 [P = 0.007], and hyaluronan [P = 0.02]), inflammation (high mobility group box-1 [P = 0.0003]), and tissue neutrophil (P = 0.0009) and macrophage (P = 0.004) infiltration. CONCLUSIONS: Together, our data confirm that the terminal pathway of complement activation plays a key role in renal IRI and demonstrate that the mechanism of injury involves shedding of the glycocalyx. Lippincott Williams & Wilkins 2019-03-25 /pmc/articles/PMC6445655/ /pubmed/30993186 http://dx.doi.org/10.1097/TXD.0000000000000881 Text en Copyright © 2019 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND) (http://creativecommons.org/licenses/by-nc-nd/4.0/) , where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
spellingShingle Basic Science
Bongoni, Anjan K.
Lu, Bo
McRae, Jennifer L.
Salvaris, Evelyn J.
Toonen, Erik J. M.
Vikstrom, Ingela
Baz Morelli, Adriana
Pearse, Martin J.
Cowan, Peter J.
Complement-mediated Damage to the Glycocalyx Plays a Role in Renal Ischemia-reperfusion Injury in Mice
title Complement-mediated Damage to the Glycocalyx Plays a Role in Renal Ischemia-reperfusion Injury in Mice
title_full Complement-mediated Damage to the Glycocalyx Plays a Role in Renal Ischemia-reperfusion Injury in Mice
title_fullStr Complement-mediated Damage to the Glycocalyx Plays a Role in Renal Ischemia-reperfusion Injury in Mice
title_full_unstemmed Complement-mediated Damage to the Glycocalyx Plays a Role in Renal Ischemia-reperfusion Injury in Mice
title_short Complement-mediated Damage to the Glycocalyx Plays a Role in Renal Ischemia-reperfusion Injury in Mice
title_sort complement-mediated damage to the glycocalyx plays a role in renal ischemia-reperfusion injury in mice
topic Basic Science
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445655/
https://www.ncbi.nlm.nih.gov/pubmed/30993186
http://dx.doi.org/10.1097/TXD.0000000000000881
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