The P2X7 receptor antagonist, oxidized adenosine triphosphate, ameliorates renal ischemia-reperfusion injury by expansion of regulatory T cells
The P2X7 receptor antagonist, oxidized adenosine triphosphate, ameliorates renal ischemia-reperfusion injury by expansion of regulatory T cells
复制标题
P2X7受体拮抗剂氧化型三磷酸腺苷通过扩增调节性T细胞减轻肾缺血再灌注损伤
DOI：
10.1016/j.kint.2017.01.031
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发表时间：
2017-08-01
影响因子：
19.6
通讯作者：
Yang, Jaeseok
中科院分区：
文献类型：
--
作者：
Koo, Tai Yeon;Lee, Jae-Ghi;Yang, Jaeseok
细胞外三磷酸腺苷（ATP）与嘌呤受体结合，作为一种危险分子，促进炎症反应。本研究旨在探讨P2 X7受体（P2 X7 R）拮抗剂高碘酸氧化型ATP（oATP）对肾缺血再灌注损伤的保护作用及其细胞机制。缺血再灌注损伤前给予oATP治疗可降低血尿素氮、血清肌酐、肾小管损伤评分和损伤后肾小管上皮细胞凋亡。树突状细胞、中性粒细胞、巨噬细胞、CD 69（+）CD 4（+）和CD 44（+）CD 4（+）T细胞的浸润减弱，但肾Foxp 3（+）CD 4（+）Treg浸润增加。oATP组IL-6和CCL 2水平降低。此外，损伤后oATP治疗改善了肾功能，减少了先天性和适应性效应细胞的浸润，并增加了Foxp 3（+）CD 4（+）T细胞的肾浸润。缺血再灌注损伤后oATP治疗增加肾小管细胞增殖，减少肾纤维化。oATP治疗减轻了RAG-1基因敲除小鼠缺血再灌注损伤后的肾功能恶化;然而，使用PC 61去除Treg消除了oATP在野生型小鼠中的有益作用。此外，在从野生型小鼠转移TclO后，oATP治疗改善了TclO对缺血再灌注损伤的有益作用，但从P2 X7 R敲除小鼠转移TclO后的治疗没有改善。P2 X7 R基因敲除小鼠的肾缺血再灌注损伤也有所减轻。使用骨髓嵌合体的实验证实，造血细胞而不是非造血细胞（如肾小管上皮细胞）上的P2 X7 R表达在缺血再灌注损伤中起主要作用。因此，oATP减轻急性肾损伤，促进肾脏缺血再灌注损伤的恢复，通过扩大TcR。
Extracellular adenosine triphosphate (ATP) binds to purinergic receptors and, as a danger molecule, promotes inflammatory responses. Here we tested whether periodate-oxidized ATP (oATP), a P2X7 receptor (P2X7R) antagonist can attenuate renal ischemia-reperfusion injury and clarify the related cellular mechanisms. Treatment with oATP prior to ischemia-reperfusion injury decreased blood urea nitrogen, serum creatinine, the tubular injury score, and tubular epithelial cell apoptosis after injury. The infiltration of dendritic cells, neutrophils, macrophages, CD69(+) CD4(+), and CD44(+) CD4(+) T cells was attenuated, but renal Foxp3(+) CD4(+) Treg infiltration was increased by oATP. The levels of IL-6 and CCL2 were reduced in the oATP group. Additionally, oATP treatment following injury improved renal function, decreased the infiltration of innate and adaptive effector cells, and increased the renal infiltration of Foxp3(+) CD4(+) Tregs. Post-ischemiareperfusion injury oATP treatment increased tubular cell proliferation and reduced renal fibrosis. oATP treatment attenuated renal functional deterioration after ischemiareperfusion injury in RAG-1 knockout mice; however, Treg depletion using PC61 abrogated the beneficial effects of oATP in wild-type mice. Furthermore, oATP treatment after transfer of Tregs from wild-type mice improved the beneficial effects of Tregs on ischemia-reperfusion injury, but treatment after transfer of Tregs from P2X7R knockout mice did not. Renal ischemia-reperfusion injury was also attenuated in P2X7R knockout mice. Experiments using bone marrow chimeras established that P2X7R expression on hematopoietic cells rather than nonhematopoietic cells, such as tubular epithelial cells, plays a major role in ischemia-reperfusion injury. Thus, oATP attenuated acute renal damage and facilitated renal recovery in ischemia-reperfusion injury by expansion of Tregs.