DNA-damaged podocyte-CD8 T cell crosstalk exacerbates kidney injury by altering DNA methylation
DNA-damaged podocyte-CD8 T cell crosstalk exacerbates kidney injury by altering DNA methylation
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DNA 损伤的足细胞-CD8 T 细胞串扰通过改变 DNA 甲基化加剧肾损伤
DOI：
10.1016/j.celrep.2023.112427
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发表时间：
2023
期刊：
影响因子：
8.8
通讯作者：
Itoh Hiroshi
中科院分区：
文献类型：
--
作者：
Nakamichi Ran;Hishikawa Akihito;Chikuma Shunsuke;Yoshimura Akihiko;Sasaki Takashi;Hashiguchi Akinori;Abe Takaya;Tokuhara Tomoko;Yoshimoto Norifumi;Nishimura Erina Sugita;Hama Eriko Yoshida;Azegami Tatsuhiko;Nakayama Takashin;Hayashi Kaori;Itoh Hiroshi
最近的表观基因组研究表明血液DNA甲基化与肾功能之间存在关联。然而，其病理学重要性仍不清楚。在这里，我们表明归巢核酸内切酶I-PpoI诱导的DNA双链断裂在肾小球足细胞引起蛋白尿，肾小球硬化，肾小管间质纤维化与DNA甲基化的变化，血细胞以及足细胞。单细胞RNA测序分析显示，肾脏中具有活化/共刺激受体NKG 2D的细胞毒性CD 8 +T细胞增加，表现出记忆前体效应细胞表型，外周循环中的CD 44高记忆CD 8 +T细胞也增加。NKG 2D阻断可减弱足细胞DNA损伤引起的肾脏表型。血液甲基化组显示STAT 1结合位点的DNA甲基化增加，STAT 1是一种有助于CD 8 +T细胞稳态的转录因子。总的来说，足细胞DNA损伤改变了血液甲基化，导致CD 8 +T细胞的变化，这有助于慢性肾脏疾病中的持续肾损伤。
Recent epigenome-wide studies suggest an association between blood DNA methylation and kidney function. However, the pathological importance remains unclear. Here, we show that the homing endonuclease I-PpoI-induced DNA double-strand breaks in kidney glomerular podocytes cause proteinuria, glomerulosclerosis, and tubulointerstitial fibrosis with DNA methylation changes in blood cells as well as in podocytes. Single-cell RNA-sequencing analysis reveals an increase in cytotoxic CD8+T cells with the activating/costimulatory receptor NKG2D in the kidneys, which exhibit a memory precursor effector cell phenotype, and the CD44highmemory CD8+T cells are also increased in the peripheral circulation. NKG2D blockade attenuates the renal phenotype caused by podocyte DNA damage. Blood methylome shows increased DNA methylation in binding sites for STAT1, a transcription factor contributing to CD8+T cell homeostasis. Collectively, podocyte DNA damage alters the blood methylome, leading to changes in CD8+T cells, which contribute to sustained renal injury in chronic kidney disease.