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Cytoskeletal protein degradation in brain death donor kidneys associates with adverse posttransplant outcomes
In brain death, cerebral injury contributes to systemic biological dysregulation, causing significant cellular stress in donor kidneys adversely impacting the quality of grafts. Here, we hypothesized that donation after brain death (DBD) kidneys undergo proteolytic processes that may deem grafts sus...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9305475/ https://www.ncbi.nlm.nih.gov/pubmed/34878723 http://dx.doi.org/10.1111/ajt.16912 |
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author | Vaughan, Rebecca H. Kresse, Jean‐Claude Farmer, Louise K. Thézénas, Marie L. Kessler, Benedikt M. Lindeman, Jan H. N. Sharples, Edward J. Welsh, Gavin I. Nørregaard, Rikke Ploeg, Rutger J. Kaisar, Maria |
author_facet | Vaughan, Rebecca H. Kresse, Jean‐Claude Farmer, Louise K. Thézénas, Marie L. Kessler, Benedikt M. Lindeman, Jan H. N. Sharples, Edward J. Welsh, Gavin I. Nørregaard, Rikke Ploeg, Rutger J. Kaisar, Maria |
author_sort | Vaughan, Rebecca H. |
collection | PubMed |
description | In brain death, cerebral injury contributes to systemic biological dysregulation, causing significant cellular stress in donor kidneys adversely impacting the quality of grafts. Here, we hypothesized that donation after brain death (DBD) kidneys undergo proteolytic processes that may deem grafts susceptible to posttransplant dysfunction. Using mass spectrometry and immunoblotting, we mapped degradation profiles of cytoskeletal proteins in deceased and living donor kidney biopsies. We found that key cytoskeletal proteins in DBD kidneys were proteolytically cleaved, generating peptide fragments, predominantly in grafts with suboptimal posttransplant function. Interestingly, α‐actinin‐4 and talin‐1 proteolytic fragments were detected in brain death but not in circulatory death or living donor kidneys with similar donor characteristics. As talin‐1 is a specific proteolytic target of calpain‐1, we investigated a potential trigger of calpain activation and talin‐1 degradation using human ex vivo precision‐cut kidney slices and in vitro podocytes. Notably, we showed that activation of calpain‐1 by transforming growth factor‐β generated proteolytic fragments of talin‐1 that matched the degradation fragments detected in DBD preimplantation kidneys, also causing dysregulation of the actin cytoskeleton in human podocytes; events that were reversed by calpain‐1 inhibition. Our data provide initial evidence that brain death donor kidneys are more susceptible to cytoskeletal protein degradation. Correlation to posttransplant outcomes may be established by future studies. |
format | Online Article Text |
id | pubmed-9305475 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-93054752022-07-28 Cytoskeletal protein degradation in brain death donor kidneys associates with adverse posttransplant outcomes Vaughan, Rebecca H. Kresse, Jean‐Claude Farmer, Louise K. Thézénas, Marie L. Kessler, Benedikt M. Lindeman, Jan H. N. Sharples, Edward J. Welsh, Gavin I. Nørregaard, Rikke Ploeg, Rutger J. Kaisar, Maria Am J Transplant ORIGINAL ARTICLES In brain death, cerebral injury contributes to systemic biological dysregulation, causing significant cellular stress in donor kidneys adversely impacting the quality of grafts. Here, we hypothesized that donation after brain death (DBD) kidneys undergo proteolytic processes that may deem grafts susceptible to posttransplant dysfunction. Using mass spectrometry and immunoblotting, we mapped degradation profiles of cytoskeletal proteins in deceased and living donor kidney biopsies. We found that key cytoskeletal proteins in DBD kidneys were proteolytically cleaved, generating peptide fragments, predominantly in grafts with suboptimal posttransplant function. Interestingly, α‐actinin‐4 and talin‐1 proteolytic fragments were detected in brain death but not in circulatory death or living donor kidneys with similar donor characteristics. As talin‐1 is a specific proteolytic target of calpain‐1, we investigated a potential trigger of calpain activation and talin‐1 degradation using human ex vivo precision‐cut kidney slices and in vitro podocytes. Notably, we showed that activation of calpain‐1 by transforming growth factor‐β generated proteolytic fragments of talin‐1 that matched the degradation fragments detected in DBD preimplantation kidneys, also causing dysregulation of the actin cytoskeleton in human podocytes; events that were reversed by calpain‐1 inhibition. Our data provide initial evidence that brain death donor kidneys are more susceptible to cytoskeletal protein degradation. Correlation to posttransplant outcomes may be established by future studies. John Wiley and Sons Inc. 2022-02-04 2022-04 /pmc/articles/PMC9305475/ /pubmed/34878723 http://dx.doi.org/10.1111/ajt.16912 Text en © 2022 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | ORIGINAL ARTICLES Vaughan, Rebecca H. Kresse, Jean‐Claude Farmer, Louise K. Thézénas, Marie L. Kessler, Benedikt M. Lindeman, Jan H. N. Sharples, Edward J. Welsh, Gavin I. Nørregaard, Rikke Ploeg, Rutger J. Kaisar, Maria Cytoskeletal protein degradation in brain death donor kidneys associates with adverse posttransplant outcomes |
title | Cytoskeletal protein degradation in brain death donor kidneys associates with adverse posttransplant outcomes |
title_full | Cytoskeletal protein degradation in brain death donor kidneys associates with adverse posttransplant outcomes |
title_fullStr | Cytoskeletal protein degradation in brain death donor kidneys associates with adverse posttransplant outcomes |
title_full_unstemmed | Cytoskeletal protein degradation in brain death donor kidneys associates with adverse posttransplant outcomes |
title_short | Cytoskeletal protein degradation in brain death donor kidneys associates with adverse posttransplant outcomes |
title_sort | cytoskeletal protein degradation in brain death donor kidneys associates with adverse posttransplant outcomes |
topic | ORIGINAL ARTICLES |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9305475/ https://www.ncbi.nlm.nih.gov/pubmed/34878723 http://dx.doi.org/10.1111/ajt.16912 |
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