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Tumor Necrosis Factor {alpha} Receptor Type 1 Activation in the Hypothalamic Paraventricular Nucleus Contributes to Glutamate Signaling and Angiotensin II-Dependent Hypertension
Journal of Neuroscience ( IF 4.4 ) Pub Date : 2021-02-10 , DOI: 10.1523/jneurosci.2360-19.2020
Clara Woods 1 , Jose Marques-Lopes 1 , Natalina H Contoreggi 1 , Teresa A Milner 1, 2 , Virginia M Pickel 1 , Gang Wang 1 , Michael J Glass 3
Affiliation  

There are significant neurogenic and inflammatory influences on blood pressure, yet the role played by each of these processes in the development of hypertension is unclear. Tumor necrosis factor α (TNFα) has emerged as a critical modulator of blood pressure and neural plasticity; however, the mechanism by which TNFα signaling contributes to the development of hypertension is uncertain. We present evidence that following angiotensin II (AngII) infusion the TNFα type 1 receptor (TNFR1) plays a key role in heightened glutamate signaling in the hypothalamic paraventricular nucleus (PVN), a key central coordinator of blood pressure control. Fourteen day administration of a slow-pressor dose of AngII in male mice was associated with transcriptional and post-transcriptional (increased plasma membrane affiliation) regulation of TNFR1 in the PVN. Further, TNFR1 was shown to be critical for elevated NMDA-mediated excitatory currents in sympathoexcitatory PVN neurons following AngII infusion. Finally, silencing PVN TNFR1 prevented the increase in systolic blood pressure induced by AngII. These findings indicate that TNFR1 modulates a cellular pathway involving an increase in NMDA-mediated currents in the PVN following AngII infusion, suggesting a mechanism whereby TNFR1 activation contributes to hypertension via heightened hypothalamic glutamate-dependent signaling.

SIGNIFICANCE STATEMENT Inflammation is critical for the emergence of hypertension, yet the mechanisms by which inflammatory mediators contribute to this dysfunction are not clearly defined. We show that tumor necrosis factor α receptor 1 (TNFR1) in the paraventricular hypothalamic nucleus (PVN), a critical neuroregulator of cardiovascular function, plays an important role in the development of hypertension in mice. In the PVN, TNFR1 expression and plasma membrane localization are upregulated during hypertension induced by angiotensin II (AngII). Further, TNFR1 activation was essential for NMDA signaling and the heightening NMDA currents during hypertension. Finally, TNFR1 silencing in the PVN inhibits elevated blood pressure induced by AngII. These results point to a critical role for hypothalamic TNFR1 signaling in hypertension.



中文翻译:

下丘脑室旁核中肿瘤坏死因子 {α} 受体 1 型激活有助于谷氨酸信号传导和血管紧张素 II 依赖性高血压

神经源性和炎症对血压有显着的影响,但这些过程在高血压发展中所起的作用尚不清楚。肿瘤坏死因子 α (TNFα) 已成为血压和神经可塑性的关键调节剂;然而,TNFα信号传导导致高血压发生的机制尚不清楚。我们提供的证据表明,输注血管紧张素 II (AngII) 后,TNFα 1 型受体 (TNFR1) 在增强下丘脑室旁核 (PVN) 的谷氨酸信号传导中发挥关键作用,PVN 是血压控制的关键中枢协调器。雄性小鼠 14 天缓慢加压剂量的 AngII 与 PVN 中 TNFR1 的转录和转录后(质膜亲和性增加)调节相关。此外,TNFR1 对 AngII 输注后交感兴奋性 PVN 神经元中 NMDA 介导的兴奋性电流升高至关重要。最后,沉默 PVN TNFR1 可阻止 AngII 诱导的收缩压升高。这些发现表明,TNFR1 调节细胞通路,涉及 AngII 输注后 NMDA 介导的 PVN 电流增加,这表明 TNFR1 激活通过增强下丘脑谷氨酸依赖性信号传导导致高血压。

意义声明炎症对于高血压的出现至关重要,但炎症介质导致这种功能障碍的机制尚不清楚。我们发现,下丘脑室旁核(PVN)中的肿瘤坏死因子α受体1(TNFR1)是心血管功能的关键神经调节因子,在小鼠高血压的发生中发挥着重要作用。在血管紧张素 II (AngII) 诱导的高血压期间,PVN 中 TNFR1 的表达和质膜定位上调。此外,TNFR1 激活对于 NMDA 信号传导和高血压期间 NMDA 电流的升高至关重要。最后,PVN 中的 TNFR1 沉默可抑制 AngII 引起的血压升高。这些结果表明下丘脑 TNFR1 信号在高血压中发挥着关键作用。

更新日期:2021-02-10
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