Activated ClC-2 Inhibits p-Akt to Repress Myelination in GDM Newborn Rats.
Activated ClC-2 Inhibits p-Akt to Repress Myelination in GDM Newborn Rats.
复制标题
激活的 ClC-2 抑制 p-Akt 抑制 GDM 新生大鼠的髓鞘形成
DOI：
10.7150/ijbs.17716
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发表时间：
2017
影响因子：
9.2
通讯作者：
Li H
中科院分区：
文献类型：
--
作者：
He F;Peng Y;Yang Z;Ge Z;Tian Y;Ma T;Li H
本研究旨在探讨2型电压门控性氯离子通道（ClC-2）对妊娠期糖尿病（GDM）新生大鼠脑白色物质髓鞘发育的影响及其机制。本研究采用晚期妊娠大鼠模型，建立GDM模型。采用RT-PCR、活性氧检测、TUNEL染色、Western Blot及免疫组化染色等方法，分析高糖对不同发育阶段脑白色质ClC-2表达的影响。结果表明，GDM组E18期后胎鼠脑白色组织中ClC-2 mRNA和蛋白表达显著增加，P0和P3期新生鼠脑白色组织中TNF-α和iNOS水平显著升高。GDM组在E18、P0、P3期白色物质中活性氧（ROS）水平明显高于对照组。P0期髓鞘转录因子Olig 2和P3期CNcl 2的表达水平均显著低于对照组。GDM组在P0、P3期胼胝体（CC）、扣带回（CG）中ClC-2表达恢复，TUNEL阳性细胞数增加。而P0期PDGFα阳性细胞数和P3期CNE表达明显减少。GDM组各脑区白色区Caspase-3表达增加，p-Akt表达受抑制。而DIDS（一种氯离子通道阻断剂）可以逆转这些变化。结论：GDM可诱导ClC-2和caspase-3的表达，从而导致细胞凋亡和髓鞘形成抑制。这种作用是通过抑制PI 3 K-Akt信号通路而实现的。应用ClC-2抑制剂DIDS对高糖所致脑白色质损伤具有保护作用。
This study aims to investigate the effect and mechanism of type 2 voltage-gated chloride channel (ClC-2) on myelin development of newborn rats' cerebral white matter with gestational diabetes mellitus (GDM). In this study, GDM model was induced in late pregnant rat model. The alteration of ClC-2 expression in various developmental stages of cerebral white matter with/without being exposed to high glucose was analyzed using RT-PCR, active oxygen detection, TUNEL staining, Western Blot as well as immuno-histochemical staining. Our results showed that ClC-2 mRNA and protein expressions in GDM group were significantly increased in white matter of fetal rats after E18 stage, and elevated the level of TNF-α and iNOS in white matter at P0 and P3 stage of newborn rats. Meanwhile, In GDM group, reactive oxygen species (ROS) levels of the white matter at E18, P0, and P3 stage were significantly higher than control group. Furthermore, the expression level of myelin transcription factor Olig2 at P0 stage and CNPase at P3 stage were strikingly lower than that of the control group. In GDM group, ClC-2 expression in the corpus callosum (CC) and cingulate gyrus (CG) regains, and TUNEL positive cell number were increased at P0 and P3 stage. However, PDGFα positive cell number at P0 stage and CNPase expression at P3 stage were significantly decreased. Caspase-3 was also increased in those white matter regions in GDM group, but p-Akt expression was inhibited. While DIDS (a chloride channel blocker) can reverse these changes. In conclusion, ClC-2 and caspase-3 were induced by GDM, which resulted in apoptosis and myelination inhibition. The effect was caused by repressing PI3K-Akt signaling pathway. Application of ClC-2 inhibitor DIDS showed protective effects on cerebral white matter damage stimulated by high glucose concentration.