Transplantation Center, Seoul National University Hospital, Seoul, Korea; Transplantation Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Transplantation Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Kidney Int. 2017 Aug;92(2):415-431. doi: 10.1016/j.kint.2017.01.031. Epub 2017 Apr 8.
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, CD69CD4, and CD44CD4 T cells was attenuated, but renal Foxp3CD4 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 Foxp3CD4 Tregs. Post-ischemia-reperfusion injury oATP treatment increased tubular cell proliferation and reduced renal fibrosis. oATP treatment attenuated renal functional deterioration after ischemia-reperfusion 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 non-hematopoietic 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.
细胞外三磷酸腺苷 (ATP) 与嘌呤能受体结合，并作为危险分子促进炎症反应。在这里，我们测试了过碘酸钠氧化的 ATP (oATP)，一种 P2X7 受体 (P2X7R) 拮抗剂是否可以减轻肾缺血再灌注损伤，并阐明相关的细胞机制。在缺血再灌注损伤前用 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。oATP 减少了树突状细胞、中性粒细胞、巨噬细胞、CD69CD4 和 CD44CD4 T 细胞的浸润，但增加了 Foxp3CD4 Treg 的浸润。oATP 组的 IL-6 和 CCL2 水平降低。此外，损伤后 oATP 治疗改善了肾功能，减少了固有和适应性效应细胞的浸润，增加了肾脏 Foxp3CD4 Treg 的浸润。缺血再灌注损伤后 oATP 治疗增加了肾小管细胞增殖，减少了肾纤维化。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 PC61 耗尽 Treg 消除了 oATP 在野生型小鼠中的有益作用。此外，从野生型小鼠转移 Treg 后 oATP 治疗改善了 Treg 对缺血再灌注损伤的有益作用，但从 P2X7R 基因敲除小鼠转移 Treg 后 oATP 治疗没有。P2X7R 基因敲除小鼠的肾缺血再灌注损伤也减轻了。使用骨髓嵌合体的实验表明，造血细胞（而非非造血细胞，如肾小管上皮细胞）上的 P2X7R 表达在缺血再灌注损伤中起主要作用。因此，oATP 通过扩增 Treg 减轻急性肾损伤并促进缺血再灌注损伤后的肾脏恢复。
