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Abstract: FR-PO172

T Cell Metabolic Programming and Protection by Glutamine Blockade in AKI

Session Information

  • AKI: Mechanisms - II
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Lee, Kyungho, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Thompson, Elizabeth A., Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Gharaie, Sepideh, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Patel, Chirag H., Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Kurzhagen, Johanna T., Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Newman-Rivera, Andrea M., Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Pierorazio, Phillip Martin, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Arend, Lois J., Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Noel, Sanjeev, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Slusher, Barbara S., Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Rabb, Hamid, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
Background

T cells participate in AKI pathogenesis. T cells are regulated by metabolic programming, less understood in AKI. Among metabolic pathways, glutaminolysis is particularly important for effector T cell function. We aimed to study kidney T cell metabolism during AKI and effects of glutamine blockade.

Methods

C57B6 mice underwent 30 min ischemia-reperfusion surgery or cisplatin injection. Germ-free (GF) mice were also studied to evaluate the effect of gut microbiota on T cell metabolism. Kidney T cells were isolated and studied by a flow cytometry-based immune-metabolic assay with interrogating artificial intelligence metabolic programs. Mice were treated with the glutamine antagonist JHU083 and effects on AKI were evaluated. Kidney sections were scored for tubular injury. In vitro studies were performed on FACS-sorted kidney T cell culture exposed to hypoxia-reoxygenation.

Results

T cells from postischemic kidneys showed a distinct T cell subset with low levels of mTOR and oxidative phosphorylation-related enzymes. Kidney T cells from GF mice exhibited global downregulation of multiple metabolic enzymes compared to those from wild-type mice. Blocking glutamine utilization with JHU083 improved functional and structural renal outcomes in ischemic (serum Cr at 24h, vehicle vs JHU083, 1.6±0.2 vs 1.1±0.1 mg/dL, P=.026; cortical necrosis, 6.6±0.9 vs 4.2±0.5 %, P=.039) and cisplatin-induced AKI (serum Cr at 72h, 2.3±0.3 vs 1.2±0.2 mg/dL, P=.016; outer medullary necrosis, 57.1±3.7 vs 19.9±4.5%, P<.001). CD4 T cells from post-AKI kidneys in JHU083 treated group were skewed toward naïve phenotypes with lower proliferation in both ischemic (CD44, 67.5±1.7 vs 56.3±1.9%, P<.001; CD62L, 29.0±1.6 vs 42.8±2.2%, P<.001; Ki67 58.7±2.9 vs 50.6±2.1%, P=.035) and nephrotoxic AKI (CD44, 50.2±3.4 vs 40.9±2.4%, P=.037; CD62L, 37.5±3.2 vs 52.5±3.0%, P=.005; Ki67, 54.4±3.6 vs 43.8±2.7%, P=.031). In vitro hypoxia-reoxygenation upregulated glycolysis-related enzymes in kidney T cells, and JHU083 inhibited CD3/CD28 stimulated proliferation.

Conclusion

AKI and as well the microbiome influence kidney T cell metabolic programming. Glutamine blockade with JHU083 improved ischemic and cisplatin-induced AKI outcomes, and is a promising novel therapeutic agent for AKI.

Funding

  • NIDDK Support