LncRNA NONRATT021972 siRNA attenuates P2X7 receptor expression and inflammatory cytokine production induced by combined high glucose and free fatty acids in PC12 cells.
LncRNA NONRATT021972 siRNA attenuates P2X7 receptor expression and inflammatory cytokine production induced by combined high glucose and free fatty acids in PC12 cells.
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LncRNA NONRATT021972 siRNA 减弱 PC12 细胞中高葡萄糖和游离脂肪酸联合诱导的 P2X7 受体表达和炎症细胞因子的产生
DOI：
10.1007/s11302-016-9500-0
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发表时间：
2016
期刊：
影响因子：
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通讯作者：
Liang Shangdong
中科院分区：
文献类型：
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作者：
Xu Hong 徐宏;He Luling;Liu Changle;Tang Lan;Xu Yonghu;Xiong Mengqi;Yang Mei;Fan Yongfang;Hu Fangfang;Liu Xingzi;Ding Lu;Gao Yun;Xu Changshui;Li Guilin;Liu Shuangmei;Wu Bing;Zou Lifang;Liang Shangdong
糖尿病神经病变(DNP)是糖尿病常见的慢性并发症，具有潜在的生命危险。近年来，高血糖和高游离脂肪酸(FFAs)被认为是糖尿病神经系统损害的主要原因。我们先前的研究表明，细胞外刺激，如高糖和/或FFA应激，可能激活p38丝裂原激活蛋白激酶(MAPK)信号通路，诱导p38 MAPK依赖的P2X7受体敏化和炎症因子在PC12细胞中的释放，但其机制尚不清楚。长非编码RNA(LncRNAs)在多种生物学过程中发挥着重要作用，包括激活一系列信号通路。在这里，我们发现联合高糖和游离脂肪酸(HGHF)诱导PC12细胞中lncRNA-NONRATT021972(NONCODE ID，nc021972)的增加。NC021972小干扰RNA(SiRNA)可抑制HGHF诱导的p38MAPK活化、P2X7受体表达和细胞内[Ca~(2+)]i升高。进一步的实验表明，nc021972与p38MAPK信号通路之间存在串扰。抑制p38MAPK信号通路可降低nc021972诱导的P2X7受体的表达，并减少[Ca~(2+)]i对P2X7受体的激活作用。同时，nc021972 siRNA抑制HGHF诱导的PC12细胞释放肿瘤坏死因子-α和IL-6，并挽救由P2X7受体介导的细胞存活率下降。因此，抑制nc021972可能成为糖尿病合并神经炎性疾病的一种新的治疗策略。
Diabetic neuropathy (DNP) is a frequent chronic complication of diabetes mellitus with potentially life-threatening outcomes. High glucose and elevated free fatty acids (FFAs) have been recently recognized as major causes of nervous system damage in diabetes. Our previous study has indicated extracellular stimuli, such as high glucose and/or FFA stress, may activate the p38 mitogen-activated protein kinase (MAPK) signaling pathway and induce a p38 MAPK-dependent sensitization of the P2X7 receptor and release of inflammatory factors in PC12 cells, while the mechanisms underlying remain to be elucidated. Long noncoding RNAs (lncRNAs) play important roles in diverse biological processes, including activation of a series of pathway signalings. Here, we showed combined highd-glucose and FFAs (HGHF) induced an increment of lncRNA-NONRATT021972 (NONCODE ID, nc021972) in PC12 cells. Nc021972 small interference RNA (siRNA) alleviated HGHF-induced activation of p38 MAPK, expression of the P2X7 receptor, and [Ca2+]iincrement upon P2X7 receptor activation. Further experiments showed that there existed a crosstalk between nc021972 and the p38 MAPK signaling pathway. Inhibition of p38 MAPK signaling decreased nc021972-induced expression of the P2X7 receptor and [Ca2+]iincrement upon P2X7 receptor activation. Also, nc021972 siRNA inhibited HGHF-induced PC12 release of TNF-α and IL-6 and rescued decreased cell viability mediated by the P2X7 receptor. Therefore, inhibition of nc021972 may serve as a novel therapeutic strategy for diabetes complicated with nervous inflammatory diseases.