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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.

TitleTumor necrosis factor alpha-receptor type 1 activation in the hypothalamic paraventricular nucleus contributes to glutamate signaling and angiotensin II-dependent hypertension.
Publication TypeJournal Article
Year of Publication2020
AuthorsWoods C, Marques-Lopes J, Contoreggi NH, Milner TA, Pickel VM, Wang G, Glass MJ
JournalJ Neurosci
Date Published2020 Dec 10
ISSN1529-2401
Abstract

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 alpha (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 the TNFα type 1 receptor (TNFR1) plays a key role in heightened glutamate signaling following slow-pressor angiotensin II (AngII) in the hypothalamic paraventricular nucleus (PVN), a key central coordinator of blood pressure control. Fourteen-day administration of a slow-pressor dose of angiotensin II (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, suggesting a mechanism whereby TNFR1 activation contributes to hypertension mediated by AngII via heightened glutamate-dependent signaling.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 alpha (TNFα) 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 potentiation of 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.

DOI10.1523/JNEUROSCI.2360-19.2020
Alternate JournalJ Neurosci
PubMed ID33303682