title: Activated ClC-2 Inhibits p-Akt to Repress Myelination in GDM Newborn Rats.
abstract: 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.
authors.affiliation: Department of Histology and Embryology, Third Military Medical University, Chongqing, China.; Battalion 5 of Cadet Brigade, Third Military Medical University, Chongqing, China.
authors.forename: Feixiang
authors.initials: F
authors.lastname: He
authors.affiliation: Battalion 4 of Cadet Brigade, Third Military Medical University, Chongqing, China.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Battalion 5 of Cadet Brigade, Third Military Medical University, Chongqing, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Battalion 5 of Cadet Brigade, Third Military Medical University, Chongqing, China.
authors.forename: Zilu
authors.initials: Z
authors.lastname: Ge
authors.affiliation: Department of Histology and Embryology, Third Military Medical University, Chongqing, China.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Histology and Embryology, Third Military Medical University, Chongqing, China.
authors.forename: Teng
authors.initials: T
authors.lastname: Ma
authors.affiliation: Department of Histology and Embryology, Third Military Medical University, Chongqing, China.
authors.forename: Hongli
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D003337:Corpus Callosum / Q000378:metabolism; D016640:Diabetes, Gestational / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006179:Gyrus Cinguli / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism*; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D062551:NAV1.2 Voltage-Gated Sodium Channel; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3
keywords: Gestational Diabetes Mellitus (GDM); apoptosis; oligodendrocyte progenitor cell (OPCs); premyelinating oligodendrocytes (Pre-OLs); type 2 voltage-gated chloride channel (ClC-2); white matter development.