Epigenetic upregulation of acid-sensing ion channel 1 contributes to gastric hypersensitivity in adult offspring rats with prenatal maternal stress
Epigenetic upregulation of acid-sensing ion channel 1 contributes to gastric hypersensitivity in adult offspring rats with prenatal maternal stress
复制标题
酸敏感离子通道 1 的表观遗传上调导致患有产前母体应激的成年后代大鼠的胃过敏。
DOI：
10.1097/j.pain.0000000000001785
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发表时间：
2020-05-01
期刊：
影响因子：
7.4
通讯作者：
Xu, Guang-Yin
中科院分区：
文献类型：
--
作者：
Wang, Hong-Jun;Xu, Xue;Xu, Guang-Yin
功能性消化不良是一种常见的功能性胃肠道疾病。胃超敏反应（GHS）是这种疾病的标志，但细胞机制仍在很大程度上未知。妊娠期的应激源可能影响子代的组织结构和功能，从而导致胃肠道疾病的发生。本研究的目的是通过检测Asic 1甲基化状态来检测产前母体应激（PMS）是否诱导GHS，并探讨酸敏感离子通道（ASIC）/核因子-κ B（NF-kappa B）信号通路的作用。通过肌电图记录检查胃扩张引起的胃敏感性。全细胞膜片钳记录技术测定神经元兴奋性的变化。通过甲基化特异性PCR和亚硫酸氢盐测序测定Asic 1的CpG岛的去甲基化。产前母亲的压力产生GHS在成年后代大鼠。阿米洛利，抑制剂的ASIC，治疗显着衰减GHS和逆转过度兴奋的胃特异性背根神经节（DRG）的神经元标记的染料DiI。ASIC 1和NF-κ Bp 65的表达在T7至T10 DRG中显著增强。此外，PMS导致Asic 1启动子中CpG岛的显著去甲基化。染色质免疫沉淀实验表明PMS还增强了NF-κ Bp 65与Asic 1基因启动子结合的能力。使用慢病毒p65 shRNA阻断NF-κ B逆转了ASIC 1表达、GHS和DRG神经元过度兴奋的上调。这些数据表明，ASIC 1表达的上调归因于Asic 1启动子DNA去甲基化和NF-κ B B激活，并且Asic 1和NF-κ Bp 65的增强的相互作用有助于PMS诱导的GHS。
Functional dyspepsia is a common functional gastrointestinal disorder. Gastric hypersensitivity (GHS) is a hallmark of this disorder, but the cellular mechanisms remain largely unknown. Stressors during gestational period could have effects on the offspring's tissue structure and function, which may predispose to gastrointestinal diseases. The aim of this study was to test whether prenatal maternal stress (PMS) induces GHS and to investigate role of acid-sensing ion channel (ASIC)/nuclear factor-kappa B (NF-kappa B) signaling by examining Asic1 methylation status in adult offspring rats. Gastric hypersensitivity in response to gastric distension was examined by electromyography recordings. Changes in neuronal excitability were determined by whole-cell patch-clamp recording techniques. Demethylation of CpG islands of Asic1 was determined by methylation-specific PCR and bisulfite sequencing assay. Prenatal maternal stress produced GHS in adult offspring rats. Treatment with amiloride, an inhibitor of ASICs, significantly attenuated GHS and reversed hyperexcitability of gastric-specific dorsal root ganglion (DRG) neurons labeled by the dye DiI. Expression of ASIC1 and NF-kappa Bp65 was markedly enhanced in T7 to T10 DRGs. Furthermore, PMS led to a significant demethylation of CpG islands in the Asic1 promoter. A chromatin immunoprecipitation assay showed that PMS also enhanced the ability of NF-kappa Bp65 to bind the promoter of Asic1 gene. Blockade of NF-kappa B using lentiviral-p65shRNA reversed upregulation of ASIC1 expression, GHS, and the hyperexcitability of DRG neurons. These data suggest that upregulation of ASIC1 expression is attributed to Asic1 promoter DNA demethylation and NF-kappa B activation, and that the enhanced interaction of the Asic1 and NF-kappa Bp65 contributes to GHS induced by PMS.