Abstract: PO0394
T Cell Metabolic Reprogramming and Effect of Glutamine Blockade in Ischemic AKI
Session Information
- AKI: Repair and Progression
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Lee, Kyungho, Johns Hopkins University, Baltimore, Maryland, United States
- Thompson, Elizabeth A., Johns Hopkins University, Baltimore, Maryland, United States
- Patel, Chirag H., Johns Hopkins University, Baltimore, Maryland, United States
- Gharaie, Sepideh, Johns Hopkins University, Baltimore, Maryland, United States
- Kurzhagen, Johanna T., Johns Hopkins University, Baltimore, Maryland, United States
- Noel, Sanjeev, Johns Hopkins University, Baltimore, Maryland, United States
- Pierorazio, Phillip M., Johns Hopkins University, Baltimore, Maryland, United States
- Slusher, Barbara S., Johns Hopkins University, Baltimore, Maryland, United States
- Rabb, Hamid, Johns Hopkins University, Baltimore, Maryland, United States
Background
T cells play an important role in the pathogenesis of AKI. Metabolic programming of T cells regulates T cell function, is a rapidly emerging field, and has not been studied in detail during AKI. We aimed to elucidate dynamics of T cell metabolism as well as the effect of blocking glutaminolysis on ischemic AKI.
Methods
We induced ischemic AKI with 30 min ischemia followed by reperfusion in C57B6 mice and harvested kidneys and spleens at multiple early time points including during ischemia. Human nonischemic and ischemic kidney tissue was obtained from nephrectomy cases. T cells were isolated and analyzed by a flow cytometry-based immune-metabolic assay with interrogating metabolic programs. The data was evaluated by computational multidimensional analyses with machine learning. The glutamine antagonist JHU083, which targets T cell metabolism, was injected intraperitoneally and effects on AKI were evaluated.
Results
Unbiased high-dimensional analyses identified a distinct T cell subset with reduced expression of mitochondrial VDAC1 and phospho-S6 ribosomal protein (pS6) in postischemic kidneys. H3K27Me3 expression, regulated by TCA cycle, drove the segregation of ischemic kidney T cells from those of nonischemic kidneys in both humans and mice. Splenic T cells from post-AKI mice showed higher expression of GLUT1, hexokinase II (HKII), and CPT1α, indicating upregulation of glycolysis and fatty acid oxidation. Blocking glutamine uptake by JHU083 treatment attenuated renal injury at 24h (plasma creatinine 1.7±0.8 vs 1.0±0.5 mg/dL, P=.03) and enhanced expression of pS6 (normalized MFI 0.38±0.07 vs 0.47±0.06, P<.01) and HKII (0.31±0.04 vs 0.41±0.05, P<.01), compared to vehicle-treated mice. Activation and proliferation were reduced in CD4 (CD44, 67±5 vs 56±6%, P<.01; Ki67, 59±9 vs 51±6%, P=.03) and CD8 T cells (CD44, 61±11 vs 41±11%, P<.01; CD69, 25±7 vs 18±4%, P=.02; Ki67, 61±13 vs 48±12%, P=.04) but increased in double-negative T cells (CD44, 94±2 vs 96±1%, P=.04; CD69, 61±8 vs 72±7%, P<.01; Ki67, 79±9% vs 91±3%, P<.01) from post-AKI kidneys of the JHU083-treated group.
Conclusion
T cells undergo distinct metabolic reprogramming during ischemic AKI. Reconstitution of metabolism by targeting the T cell glutamine pathway could be a promising therapeutic approach for AKI.
Funding
- NIDDK Support