长时间的细胞外低钠血症以及随后的快速纠正会调节小胶质细胞中依赖于 NFAT5 的一氧化氮的产生。

IF 7.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Free Radical Biology and Medicine Pub Date : 2024-08-21 DOI:10.1016/j.freeradbiomed.2024.08.019
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引用次数: 0

摘要

低钠血症是最常见的临床电解质紊乱。最近有报道称,慢性低钠血症与跌倒、骨折、骨质疏松症、神经认知障碍和精神表现有关。在治疗慢性低钠血症时,过快地纠正低钠血症会导致渗透性脱髓鞘综合征(ODS),这是一种中枢性脱髓鞘疾病,也与神经系统的发病率和死亡率有关。我们曾利用大鼠模型表明,小胶质细胞在 ODS 的发病机制中起着关键作用。然而,快速纠正低钠血症对小胶质细胞的直接影响尚不清楚。此外,慢性低钠血症对小胶质细胞的影响仍然难以捉摸。利用小胶质细胞系 BV-2 和 6-3,我们在此表明,低细胞外钠浓度(降低 36 毫摩尔/升;LS)会抑制小胶质细胞的 Nos2 mRNA 表达和一氧化氮(NO)产生。在快速纠正低钠浓度时,这两种细胞中的一氧化氮产生量均显著增加,这表明急性纠正低钠血症部分直接导致了 Nos2 mRNA 表达和一氧化氮释放在 ODS 病理生理学中的增加。LS还抑制了活化T细胞核因子-5(NFAT5)的表达和核转位,NFAT5是一种转录因子,可调节参与渗透压应激的基因的表达。此外,过表达 NFAT5 能显著增加 BV-2 细胞中 Nos2 mRNA 的表达和 NO 的产生。从慢性低钠血症模型小鼠大脑皮层分离出的小胶质细胞中,Nos2 和 Nfat5 mRNA 的表达也受到调节。这些数据表明,LS调节小胶质细胞NO的产生依赖于NFAT5,并表明小胶质细胞对低钠血症诱导的神经元功能障碍有贡献。
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Prolonged extracellular low sodium concentrations and subsequent their rapid correction modulate nitric oxide production dependent on NFAT5 in microglia

Hyponatremia is the most common clinical electrolyte disorder. Chronic hyponatremia has been recently reported to be associated with falls, fracture, osteoporosis, neurocognitive impairment, and mental manifestations. In the treatment of chronic hyponatremia, overly rapid correction of hyponatremia can cause osmotic demyelination syndrome (ODS), a central demyelinating disease that is also associated with neurological morbidity and mortality. Using a rat model, we have previously shown that microglia play a critical role in the pathogenesis of ODS. However, the direct effect of rapid correction of hyponatremia on microglia is unknown. Furthermore, the effect of chronic hyponatremia on microglia remains elusive. Using microglial cell lines BV-2 and 6-3, we show here that low extracellular sodium concentrations (36 mmol/L decrease; LS) suppress Nos2 mRNA expression and nitric oxide (NO) production of microglia. On rapid correction of low sodium concentrations, NO production was significantly increased in both cells, suggesting that acute correction of hyponatremia partly directly contributes to increased Nos2 mRNA expression and NO release in ODS pathophysiology. LS also suppressed expression and nuclear translocation of nuclear factor of activated T cells-5 (NFAT5), a transcription factor that regulates the expression of genes involved in osmotic stress. Furthermore, overexpression of NFAT5 significantly increased Nos2 mRNA expression and NO production in BV-2 cells. Expressions of Nos2 and Nfat5 mRNA were also modulated in microglia isolated from cerebral cortex in chronic hyponatremia model mice. These data indicate that LS modulates microglial NO production dependent on NFAT5 and suggest that microglia contribute to hyponatremia-induced neuronal dysfunctions.

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来源期刊
Free Radical Biology and Medicine
Free Radical Biology and Medicine 医学-内分泌学与代谢
CiteScore
14.00
自引率
4.10%
发文量
850
审稿时长
22 days
期刊介绍: Free Radical Biology and Medicine is a leading journal in the field of redox biology, which is the study of the role of reactive oxygen species (ROS) and other oxidizing agents in biological systems. The journal serves as a premier forum for publishing innovative and groundbreaking research that explores the redox biology of health and disease, covering a wide range of topics and disciplines. Free Radical Biology and Medicine also commissions Special Issues that highlight recent advances in both basic and clinical research, with a particular emphasis on the mechanisms underlying altered metabolism and redox signaling. These Special Issues aim to provide a focused platform for the latest research in the field, fostering collaboration and knowledge exchange among researchers and clinicians.
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