α2δ-1–Dependent NMDA Receptor Activity in the Hypothalamus Is an Effector of Genetic-Environment Interactions That Drive Persistent Hypertension
| العنوان: | α2δ-1–Dependent NMDA Receptor Activity in the Hypothalamus Is an Effector of Genetic-Environment Interactions That Drive Persistent Hypertension |
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| المؤلفون: | Jian Ying Shao, De Pei Li, Jing-Jing Zhou, Hui Lin Pan, Shao Rui Chen |
| المصدر: | J Neurosci |
| بيانات النشر: | Society for Neuroscience, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Male, medicine.medical_specialty, Sympathetic nervous system, Calcium Channels, L-Type, Rats, Inbred WKY, Receptors, N-Methyl-D-Aspartate, Rats, Inbred SHR, Internal medicine, Animals, Medicine, Genetic Predisposition to Disease, Chronic stress, Research Articles, Neuronal Plasticity, business.industry, General Neuroscience, Memantine, Neurogenic hypertension, Rats, Autonomic nervous system, medicine.anatomical_structure, Endocrinology, nervous system, Hypothalamus, Hypertension, Synaptic plasticity, NMDA receptor, Female, Gene-Environment Interaction, business, Stress, Psychological, Paraventricular Hypothalamic Nucleus, medicine.drug |
| الوصف: | The interplay between genetic and environmental factors is critically involved in hypertension development. The paraventricular nucleus (PVN) of the hypothalamus regulates sympathetic output during stress responses and chronic hypertension. In this study, we determined mechanisms of synaptic plasticity in the PVN in chronic stress-induced persistent hypertension in male borderline hypertensive rats (BHR), the first offspring of spontaneously hypertensive rats and normotensive Wistar-Kyoto rats. In Wistar-Kyoto rats, chronic unpredictable mild stress (CUMS) increased arterial blood pressure (ABP), which quickly returned to baseline after CUMS ended. In contrast, in BHR, CUMS caused persistent elevation in ABP, which lasted at least 2 weeks after CUMS ended. CUMS also increased the mRNA level of α2δ-1 and synaptic protein levels of GluN1, α2δ-1, and α2δ-1–GluN1 complexes in the PVN in BHR. Furthermore, CUMS significantly increased the frequency of miniature excitatory postsynaptic currents and the amplitude of NMDA receptor currents in spinally projecting PVN neurons in BHR; these increases were normalized by blocking NMDA receptors with AP5, inhibiting α2δ-1 with gabapentin, or disrupting the α2δ-1–NMDA receptor interaction with α2δ-1Tat peptide. Microinjection of AP5 or α2δ-1Tat peptide into the PVN normalized elevated ABP and renal sympathetic nerve activity in stressed BHR. In addition, systemically administered gabapentin or memantine attenuated higher ABP induced by CUMS in BHR. Our findings indicate that chronic stress-induced persistent hypertension is mediated by augmented sympathetic outflow via α2δ-1–bound NMDA receptors in the PVN. This new information provides a cellular and molecular basis for how the genetic-environment interactions cause persistent hypertension. Significance Statement: Chronic stress is a major risk factor for hypertension development, especially for individuals with a genetic predisposition to hypertension. Using a rat model of borderline hypertension, we showed that chronic stress induced long-lasting hypertension and sympathetic nerve hyperactivity, which were maintained by NMDA receptor activation in the hypothalamus. Chronic stress also increased the expression of α2δ-1, previously regarded as a Ca2+ channel subunit, promoting physical interaction with and synaptic trafficking of NMDA receptors in the hypothalamus. Inhibiting α2δ-1, blocking NMDA receptors, or disrupting α2δ-1–bound NMDA receptors reversed chronic stress-induced sympathetic outflow and persistent hypertension. Thus, α2δ-1–dependent NMDA receptor activity in the hypothalamus is an effector of genetic-environment interactions and may be targeted for treating stress-induced neurogenic hypertension. |
| تدمد: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.0346-21.2021 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b3932c21028859fbfc2536bc5b43f2e1 https://doi.org/10.1523/jneurosci.0346-21.2021 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....b3932c21028859fbfc2536bc5b43f2e1 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15292401 02706474 |
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| DOI: | 10.1523/jneurosci.0346-21.2021 |