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首页> 外文期刊>American Journal of Physiology >ATP induces PAD4 in renal proximal tubule cells via P2X7 receptor activation to exacerbate ischemic AKI
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ATP induces PAD4 in renal proximal tubule cells via P2X7 receptor activation to exacerbate ischemic AKI

机译：ATP在肾近端小管细胞中通过P2X7受体激活诱导PAD4，以加剧缺血性AKI

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We previously demonstrated that renal tubular peptidylarginine deiminase-4 (PAD4) is induced after ischemia-repeifusion (IR) injury and this induction of PAD4 exacerbates ischemic acute kidney injury (AKI) by promoting renal tubular inflammation and neutrophil infiltration. However, the mechanisms of renal tubular PAD4 induction after IR remain unknown. Here, we tested the hypothesis that ATP, a proinflammatory danger-associated molecular pattern (DAMP) ligand released from necrotic cells after IR injury, induces renal tubular PAD4 and exacerbates ischemic AKI via P2 purinergic receptor activation. ATP as well as ATP-γS (a nonme-tabolizable ATP analog) induced PAD4 mRNA, protein, and activity in human and mouse renal proximal tubule cells. Supporting the hypothesis that ATP induces renal tubular PAD4 via P2X7 receptor activation, A804598 (a selective P2X7 receptor antagonist) blocked the ATP-mediated induction of renal tubular PAD4 whereas BzATP (a selective P2X7 receptor agonist) mimicked the effects of ATP by inducing renal tubular PAD4 expression and activity. Moreover, ATP-mediated calcium influx in renal proximal tubule cells was blocked by A804598 and was mimicked by BzATP. P2X7 activation by BzATP also induced PAD4 expression and activity in mouse kidney in vivo. Finally, supporting a critical role for PAD4 in P2X7-mediated exacerbation of renal injury, BzATP exacerbated ischemic AKI in PAD4 wild-type mice but not in PAD4-deficient mice. Taken together, our studies show that ATP induces renal tubular PAD4 via P2X7 receptor activation to exacerbate renal tubular inflammation and injury after IR.
机译：我们以前证明肾小管肽氨基喹啉-4（PAD4）在缺血 - 沉积物（IR）损伤后诱导，并且通过促进肾小管炎症和中性粒细胞浸润，这种乳头4诱导加剧了缺血性急性肾损伤（AKI）。然而，IR后肾小管垫4诱导的机制仍然未知。在这里，我们测试了ATP，促炎危险相关分子图案（潮湿）配体的假设，在IR损伤后从坏死细胞中释放，诱导肾小管垫4并通过P2嘌呤能受体活化加剧缺血性AKI。 ATP以及ATP-γs（非贝氏曲调ATP模拟）诱导的PAD4 mRNA，蛋白质和在人和小鼠肾近端小管细胞中的活性。支持ATP通过P2X7受体激活诱导肾小管垫4的假设，A804598（一种选择性P2X7受体拮抗剂）阻断了ATP介导的肾小管垫4的诱导，而BZATP（选择性P2X7受体激动剂）通过诱导肾小管模仿ATP的作用PAD4表达和活动。此外，肾近端小管细胞中的ATP介导的钙流入由A804598封闭，并通过BZATP模仿。 BZATP的P2X7活化在体内诱导小鼠肾脏的乳头4表达和活性。最后，支持PAP4在P2X7介导的肾损伤中的关键作用，BZATP在PAD4野生型小鼠中加剧了缺血性，但不在PAD4缺陷小鼠中。我们的研究表明，ATP通过P2X7受体激活诱导肾小管垫4加剧IR后加剧肾小管炎症和损伤。

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