Abstract
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.
Authors
Kyungho Lee, Elizabeth A. Thompson, Sepideh Gharaie, Chirag H. Patel, Johanna T. Kurzhagen, Phillip M. Pierorazio, Lois J. Arend, Ajit G. Thomas, Sanjeev Noel, Barbara S. Slusher, Hamid Rabb
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