T cell metabolic reprogramming in acute kidney injury and protection by glutamine blockade.
T cell metabolic reprogramming in acute kidney injury and protection by glutamine blockade.
复制标题
急性肾损伤中的 T 细胞代谢重编程和谷氨酰胺阻断的保护。
DOI：
10.1172/jci.insight.160345
复制
发表时间：
2023-06-22
期刊：
影响因子：
8
通讯作者：
Rabb, Hamid
中科院分区：
文献类型：
--
作者：
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细胞在急性肾损伤（AKI）中起重要作用。T细胞的代谢编程调节其功能，是一个迅速兴起的领域，在AKI中尚不清楚。我们在C57BL/6J小鼠中诱导缺血性AKI，并在多个时间点采集肾脏和脾脏。T细胞分离并通过免疫代谢试验进行分析。无偏机器学习分析确定了aki后肾脏中具有电压依赖性阴离子通道1和mTOR表达降低的独特T细胞亚群。缺血肾组蛋白H3、赖氨酸27和谷氨酰胺酶三甲基化表达较高。aki后小鼠脾T细胞中葡萄糖转运蛋白1、己糖激酶II和肉毒碱棕榈酰转移酶1a的表达较高。人类非缺血和缺血肾组织与小鼠肾脏显示相似的结果。鉴于谷氨酰胺在T细胞代谢途径中的聚合作用以及相对安全的谷氨酰胺拮抗剂JHU083的可用性，评估了对AKI的影响。JHU083减轻了缺血性和肾毒性AKI的肾损伤，降低了T细胞的活化和增殖，而谷氨酰胺阻断对T细胞缺陷小鼠没有保护作用。体外缺氧表现出糖酵解相关酶的上调。在AKI过程中，T细胞发生代谢重编程，通过靶向T细胞谷氨酰胺途径重建代谢可能是一种很有前景的新治疗方法。
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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DOI：
10.1172/jci148546
发表时间：
2022-01-04
期刊：
The Journal of clinical investigation
影响因子：
--
作者：
Corrado M;Pearce EL
通讯作者：
Pearce EL
影响因子：
81.5
作者：
Kellum, John A.;Romagnani, Paola;Anders, Hans-Joachim
通讯作者：
Anders, Hans-Joachim
影响因子：
64.5
作者：
Buck MD;Sowell RT;Kaech SM;Pearce EL
通讯作者：
Pearce EL
影响因子：
64.5
作者：
Johnson MO;Wolf MM;Madden MZ;Andrejeva G;Sugiura A;Contreras DC;Maseda D;Liberti MV;Paz K;Kishton RJ;Johnson ME;de Cubas AA;Wu P;Li G;Zhang Y;Newcomb DC;Wells AD;Restifo NP;Rathmell WK;Locasale JW;Davila ML;Blazar BR;Rathmell JC
通讯作者：
Rathmell JC
DOI：
10.1152/ajprenal.00246.2011
发表时间：
2012-01-01
影响因子：
4.2
作者：
Hu, Ya-Mei;Pai, Man-Hui;Yeh, Sung-Ling
通讯作者：
Yeh, Sung-Ling