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T cell metabolic reprogramming in acute kidney injury and protection by glutamine blockade

T cells play an important role in acute kidney injury (AKI). Metabolic programming of T cells regulates their function, is a rapidly emerging field, and is unknown in AKI. We induced ischemic AKI in C57BL/6J mice and collected kidneys and spleens at multiple time points. T cells were isolated and an...

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Autores principales: Lee, Kyungho, Thompson, Elizabeth A., Gharaie, Sepideh, Patel, Chirag H., Kurzhagen, Johanna T., Pierorazio, Phillip M., Arend, Lois J., Thomas, Ajit G., Noel, Sanjeev, Slusher, Barbara S., Rabb, Hamid
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10371253/
https://www.ncbi.nlm.nih.gov/pubmed/37166984
http://dx.doi.org/10.1172/jci.insight.160345
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author Lee, Kyungho
Thompson, Elizabeth A.
Gharaie, Sepideh
Patel, Chirag H.
Kurzhagen, Johanna T.
Pierorazio, Phillip M.
Arend, Lois J.
Thomas, Ajit G.
Noel, Sanjeev
Slusher, Barbara S.
Rabb, Hamid
author_facet Lee, Kyungho
Thompson, Elizabeth A.
Gharaie, Sepideh
Patel, Chirag H.
Kurzhagen, Johanna T.
Pierorazio, Phillip M.
Arend, Lois J.
Thomas, Ajit G.
Noel, Sanjeev
Slusher, Barbara S.
Rabb, Hamid
author_sort Lee, Kyungho
collection PubMed
description T cells play an important role in acute kidney injury (AKI). Metabolic programming of T cells regulates their function, is a rapidly emerging field, and is unknown in AKI. We induced ischemic AKI in C57BL/6J mice and collected kidneys and spleens at multiple time points. T cells were isolated and analyzed by an immune-metabolic assay. Unbiased machine learning analyses identified a distinct T cell subset with reduced voltage-dependent anion channel 1 and mTOR expression in post-AKI kidneys. Ischemic kidneys showed higher expression of trimethylation of histone H3 lysine 27 and glutaminase. Splenic T cells from post-AKI mice had higher expression of glucose transporter 1, hexokinase II, and carnitine palmitoyltransferase 1a. Human nonischemic and ischemic kidney tissue displayed similar findings to mouse kidneys. Given a convergent role for glutamine in T cell metabolic pathways and the availability of a relatively safe glutamine antagonist, JHU083, effects on AKI were evaluated. JHU083 attenuated renal injury and reduced T cell activation and proliferation in ischemic and nephrotoxic AKI, whereas T cell–deficient mice were not protected by glutamine blockade. In vitro hypoxia demonstrated upregulation of glycolysis-related enzymes. T cells undergo metabolic reprogramming during AKI, and reconstitution of metabolism by targeting T cell glutamine pathway could be a promising novel therapeutic approach.
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spelling pubmed-103712532023-07-27 T cell metabolic reprogramming in acute kidney injury and protection by glutamine blockade Lee, Kyungho Thompson, Elizabeth A. Gharaie, Sepideh Patel, Chirag H. Kurzhagen, Johanna T. Pierorazio, Phillip M. Arend, Lois J. Thomas, Ajit G. Noel, Sanjeev Slusher, Barbara S. Rabb, Hamid JCI Insight Research Article T cells play an important role in acute kidney injury (AKI). Metabolic programming of T cells regulates their function, is a rapidly emerging field, and is unknown in AKI. We induced ischemic AKI in C57BL/6J mice and collected kidneys and spleens at multiple time points. T cells were isolated and analyzed by an immune-metabolic assay. Unbiased machine learning analyses identified a distinct T cell subset with reduced voltage-dependent anion channel 1 and mTOR expression in post-AKI kidneys. Ischemic kidneys showed higher expression of trimethylation of histone H3 lysine 27 and glutaminase. Splenic T cells from post-AKI mice had higher expression of glucose transporter 1, hexokinase II, and carnitine palmitoyltransferase 1a. Human nonischemic and ischemic kidney tissue displayed similar findings to mouse kidneys. Given a convergent role for glutamine in T cell metabolic pathways and the availability of a relatively safe glutamine antagonist, JHU083, effects on AKI were evaluated. JHU083 attenuated renal injury and reduced T cell activation and proliferation in ischemic and nephrotoxic AKI, whereas T cell–deficient mice were not protected by glutamine blockade. In vitro hypoxia demonstrated upregulation of glycolysis-related enzymes. T cells undergo metabolic reprogramming during AKI, and reconstitution of metabolism by targeting T cell glutamine pathway could be a promising novel therapeutic approach. American Society for Clinical Investigation 2023-06-22 /pmc/articles/PMC10371253/ /pubmed/37166984 http://dx.doi.org/10.1172/jci.insight.160345 Text en © 2023 Lee et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Lee, Kyungho
Thompson, Elizabeth A.
Gharaie, Sepideh
Patel, Chirag H.
Kurzhagen, Johanna T.
Pierorazio, Phillip M.
Arend, Lois J.
Thomas, Ajit G.
Noel, Sanjeev
Slusher, Barbara S.
Rabb, Hamid
T cell metabolic reprogramming in acute kidney injury and protection by glutamine blockade
title T cell metabolic reprogramming in acute kidney injury and protection by glutamine blockade
title_full T cell metabolic reprogramming in acute kidney injury and protection by glutamine blockade
title_fullStr T cell metabolic reprogramming in acute kidney injury and protection by glutamine blockade
title_full_unstemmed T cell metabolic reprogramming in acute kidney injury and protection by glutamine blockade
title_short T cell metabolic reprogramming in acute kidney injury and protection by glutamine blockade
title_sort t cell metabolic reprogramming in acute kidney injury and protection by glutamine blockade
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10371253/
https://www.ncbi.nlm.nih.gov/pubmed/37166984
http://dx.doi.org/10.1172/jci.insight.160345
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