ATP-P2X4 signaling mediates NLRP3 inflammasome activation: A novel pathway of diabetic nephropathy
ATP-P2X4 signaling mediates NLRP3 inflammasome activation: A novel pathway of diabetic nephropathy
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ATP-P2X4 信号传导介导 NLRP3 炎性体激活：糖尿病肾病的新途径。
DOI：
10.1016/j.biocel.2013.02.009
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发表时间：
2013-05-01
影响因子：
4
通讯作者：
He, Yani
中科院分区：
文献类型：
--
作者：
Chen, Kehong;Zhang, Jianguo;He, Yani
肾小管间质炎症在糖尿病肾病（DN）的发展中起着关键作用。 IL-1 家族中的细胞因子是肾小管间质炎症的关键促炎细胞因子。细胞外ATP可引起P2X受体激活NOD样受体3（NLRP3）炎性体并引起IL-1β和IL-18成熟和释放。我们研究了 ATP-P2X4 信号传导在 NLRP3 炎症小体激活和 DN 肾间质炎症特征中的作用。离体研究显示，与对照组相比，2 型糖尿病肾病患者的肾小管上皮细胞中 P2X4 的表达增加。线性相关分析显示P2X4表达量与尿IL-1p、IL-18水平呈正相关。此外，P2X4 表达与 NLRP3、IL-1β 和 IL-18 表达共定位。体外培养实验显示，高糖刺激后HK-2细胞中NLRP3蛋白表达、caspase-1和IL-1β裂解以及IL-1β、IL-18和ATP释放显着增加。然而，消耗细胞外ATP的腺苷三磷酸双磷酸酶完全阻断了高葡萄糖引起的变化。 P2受体拮抗剂苏拉明、P2X受体拮抗剂TNP-ATP、P2X4选择性拮抗剂5-BDBD和P2X4基因沉默减弱了高糖诱导的NLRP3表达、caspase-1和IL-1β的裂解以及IL-1β和IL-18的释放。综上所述，这些结果表明 ATP-P2X4 信号传导介导高葡萄糖诱导的 NLRP3 炎症小体激活，调节 IL-1 家族细胞因子分泌，并导致 DN 中肾小管间质炎症的发生。 (C) 2013 Elsevier Ltd. 保留所有权利。
Tubulointerstitial inflammation plays a key role in the development of diabetic nephropathy (DN). Cytokines in the IL-1 family are the key pro-inflammatory cytokines of tubulointerstitial inflammation. Extracellular ATP can cause P2X receptors to activate the NOD-like receptor 3 (NLRP3) inflammasome and cause IL-1 beta and IL-18 maturation and release. We investigated the role of ATP-P2X4 signaling in NLRP3 inflammasome activation and renal interstitial inflammation characteristic of DN. Ex vivo studies, P2X4 showed increased expression in renal tubule epithelial cells in patients with nephropathy due to type 2 diabetes compared to those in the control group. Linear correlation analysis shows that P2X4 expression was positively related with urine IL-1 p and IL-18 levels. Moreover, P2X4 expression was co-localized with NLRP3, IL-1 beta, and IL-18 expression. In vitro culture experiments showed NLRP3 protein expression, cleavage of caspase-1 and IL-1 beta, and release of IL-1 beta, IL-18 and ATP in HK-2 cells significantly increased after high glucose stimulation. However, apyrase, which consumes extracellular ATP, completely blocked the changes caused by high glucose. The P2 receptor antagonist suramin, P2X receptor antagonist TNP-ATP, P2X4 selective antagonist 5-BDBD, and P2X4 gene silencing attenuated NLRP3 expression, cleavage of caspase-1 and IL-1 beta, and release of IL-1 beta and IL-18 induced by high glucose. Taken together, these results suggest that ATP-P2X4 signaling mediates high glucose-induced activation of the NLRP3 inflammasome, regulates IL-1 family cytokine secretion, and causes the development of tubulointerstitial inflammation in DN. (C) 2013 Elsevier Ltd. All rights reserved.