P2X7 receptor signaling promotes inflammation in renal parenchymal cells suffering from ischemia-reperfusion injury.
P2X7 receptor signaling promotes inflammation in renal parenchymal cells suffering from ischemia-reperfusion injury.
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P2X7受体信号传导促进缺血再灌注损伤肾实质细胞的炎症
DOI：
10.1038/s41419-020-03384-y
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发表时间：
2021-01-27
影响因子：
9
通讯作者：
Gu L
中科院分区：
文献类型：
--
作者：
Qian Y;Qian C;Xie K;Fan Q;Yan Y;Lu R;Wang L;Zhang M;Wang Q;Mou S;Dai H;Ni Z;Pang H;Gu L
细胞外三磷酸腺苷（adenosine triphosphate，ATP）及其受体P2 X7受体（P2 X7 R）在肾缺血再灌注损伤的病理过程中起重要作用，但其机制尚不清楚。肾小管上皮细胞表达的P2 X7受体在缺血性急性肾损伤中的作用尚不清楚。本研究的目的是阐明这一机制是否涉及激活肾小管上皮细胞中的核苷酸结合寡聚化结构域样受体蛋白3（NLRP 3）炎性小体。在我们的研究中，我们使用了雄性C57 BL/6野生型和P2 X7 R（−/−）小鼠，培养的人近端肾小管上皮细胞和急性肾损伤患者的肾脏。小鼠行单侧肾切除联合侧肾蒂钳夹术。培养的细胞进行缺氧/复氧或ATP。腺苷三磷酸双磷酸酶和A438079用于阻断细胞外ATP/P2 X7受体途径。我们还通过使用P2 X7 R（-/-）小鼠和P2 X7 R（+/+）野生型小鼠构建了辐射诱导的骨髓（BM）嵌合体。P2 X7受体缺陷可保护肾缺血再灌注损伤，并减少NLRP 3炎性小体的形成。通过使用BM嵌合体，我们发现与野生型BM到野生型受体组相比，野生型BM到P2 X7 R（−/−）受体组的血清肌酐部分降低，组织学损伤较少。在肾小管上皮细胞中，缺氧/复氧诱导ATP释放，细胞外ATP耗竭降低活性IL-1β的表达。ATP激活肾小管上皮细胞中的NLRP 3炎性小体，其被P2 X7受体的瞬时沉默以及用A438079阻断P2 X7受体所钝化。在人类样本中，我们发现3期阿基患者的P2 X7受体表达水平高于1期或2期患者。细胞外ATP/P2 X7受体轴阻断可能通过调节NLRP 3炎性体对肾小管上皮细胞缺血再灌注损伤具有保护作用。
Extracellular adenosine triphosphate (ATP) and its receptor, P2X7 receptor (P2X7R), are playing an important role in the pathological process of renal ischemia-reperfusion injury, but their underlying mechanism remains unclear. Also, the effects of tubular epithelium-expressed P2X7 receptor on ischemia acute kidney injury is still unknown. The aim of this study is to clarify if this mechanism involves the activation of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in the renal tubular epithelial cells. In our research, we used male C57BL/6 wild type and P2X7R (−/−) mice, cultured human proximal tubular epithelial cells, and kidneys from acute kidney injury patients. Mice underwent for unilateral nephrectomy combined with the lateral renal pedicle clamping. Cultured cells were subjected to hypoxia/reoxygenation or ATP. Apyrase and A438079 were used to block the extracellular ATP/P2X7 receptor pathway. We also constructed radiation-induced bone marrow (BM) chimeras by using P2X7R (−/−) mice and P2X7R (+/+) wild-type mice. P2X7 receptor deficiency protected from renal ischemia-reperfusion injury and attenuated the formation of NLRP3 inflammasome. By using BM chimeras, we found a partial reduction of serum creatinine and less histological impairment in group wild-type BM to P2X7R (−/−) recipient, compared with group wild-type BM to wild-type recipient. In renal tubular epithelial cells, hypoxia/reoxygenation induced ATP release and extracellular ATP depletion reduced the expression of active IL-1β. ATP activated the NLRP3 inflammasome in renal tubular epithelial cells, which were blunted by transient silence of P2X7 receptor, as well as by P2X7 receptor blocking with A438079. In human samples, we found that patients with Stage 3 AKI had higher levels of P2X7 receptor expression than patients with Stage 1 or Stage 2. Extracellular ATP/P2X7 receptor axis blocking may protect renal tubular epithelial cells from ischemia-reperfusion injury through the regulation of NLRP3 inflammasome.
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