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Estrogen receptor-? in the paraventricular nucleus and rostroventrolateral medulla plays an essential protective role in aldosterone/salt-induced hypertension in female rats.

ABSTRACT: The identification of the specific estrogen receptor (ER) subtypes that are involved in estrogen protection from hypertension and their specific locations in the central nervous system is critical to our understanding and design of effective estrogen replacement therapies in women. Using selective ER agonists and recombinant adeno-associated virus (AAV) carrying small interference (si) RNA to silence either ER? (AAV-siRNA-ER?) or ER? (AAV-siRNA-ER?), the present study investigated regional specificity of different ER subtypes in the protective actions of estrogen in aldosterone (Aldo)-induced hypertension. Intracerebroventricular infusions of either diarylpropionitrile, a selective ER? agonist, or propyl-pyrazole-triol, a selective ER? agonist, attenuated Aldo/NaCl-induced hypertension in ovariectomized rats. In contrast, intracerebroventricular injections of siRNA-ER? or siRNA-ER? augmented Aldo-induced hypertension in intact females. Site-specific paraventricular nucleus (PVN) or rostroventrolateral medulla (RVLM) injections of siRNA-ER? augmented Aldo-induced hypertension. However, rats with PVN or RVLM injections of siRNA-ER? did not significantly increase blood pressure induced by Aldo. Real-time polymerase chain reaction analyses of the PVN and RVLM of siRNA-injected rat confirmed a marked reduction in the expression of ER? and ER?. In cultured PVN neurons, silencing either ER? or ER? by culturing PVN neurons with siRNA-ER? or siRNA-ER? enhanced Aldo-induced reactive oxygen species production. Ganglionic blockade after Aldo infusion showed an increase in sympathetic activity in ER? knockdown rats. These results indicate that both PVN and RVLM ER?, but not ER? in these nuclei, contribute to the protective effects of estrogen against Aldo-induced hypertension. The brain regions responsible for the protective effects of estrogen interaction with ER? in Aldo-induced hypertension still need to be determined.

SUBMITTER: Xue B

PROVIDER: S-EPMC3893074 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Estrogen receptor-β in the paraventricular nucleus and rostroventrolateral medulla plays an essential protective role in aldosterone/salt-induced hypertension in female rats.

Xue Baojian B Zhang Zhongming Z Beltz Terry G TG Johnson Ralph F RF Guo Fang F Hay Meredith M Johnson Alan Kim AK

Hypertension (Dallas, Tex. : 1979) 20130422 6

The identification of the specific estrogen receptor (ER) subtypes that are involved in estrogen protection from hypertension and their specific locations in the central nervous system is critical to our understanding and design of effective estrogen replacement therapies in women. Using selective ER agonists and recombinant adeno-associated virus (AAV) carrying small interference (si) RNA to silence either ERα (AAV-siRNA-ERα) or ERβ (AAV-siRNA-ERβ), the present study investigated regional speci ...[more]

PMID: 23608653

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Project description:New findings• What is the central question of this study? We hypothesized that central inflammatory processes that involve activation of microglia and astrocytes contribute to the development of Gαi2 protein-dependent, salt-sensitive hypertension. • What is the main finding and its importance? The main finding is that PVN-specific inflammatory processes, driven by microglial activation, appear to be linked to the development of Gαi2 protein-dependent, salt-sensitive hypertension in Sprague-Dawley rats. This finding might reveal new mechanistic targets in the treatment of hypertension.AbstractThe central mechanisms underlying salt-sensitive hypertension, a significant public health issue, remain to be established. Researchers in our laboratory have reported that hypothalamic paraventricular nucleus (PVN) Gαi2 proteins mediate the sympathoinhibitory and normotensive responses to high sodium intake in salt-resistant rats. Given the recent evidence of central inflammation in animal models of hypertension, we hypothesized that PVN inflammation contributes to Gαi2 protein-dependent, salt-sensitive hypertension. Male Sprague-Dawley rats received chronic intracerebroventricular infusions of a targeted Gαi2 or control scrambled oligodeoxynucleotide (ODN) and were maintained for 7 days on a normal-salt (NS; 0.6% NaCl) or high-salt (HS; 4% NaCl) diet; in subgroups on HS, intracerebroventricular minocycline (microglial inhibitor) was co-infused with ODNs. Radiotelemetry was used in subgroups of rats to measure mean arterial pressure (MAP) chronically. In a separate group of rats, plasma noradrenaline, plasma renin activity, urinary angiotensinogen and mRNA levels of the PVN pro-inflammatory cytokines TNFα, IL-1β and IL-6 and the anti-inflammatory cytokine IL-10 were assessed. In additional groups, immunohistochemistry was performed for markers of PVN and subfornical organ microglial activation and cytokine levels and PVN astrocyte activation. High salt intake evoked salt-sensitive hypertension, increased plasma noradrenaline, PVN pro-inflammatory cytokine mRNA upregulation, anti-inflammatory cytokine mRNA downregulation and PVN-specific microglial activation in rats receiving a targeted Gαi2 but not scrambled ODN. Minocycline co-infusion significantly attenuated the increase in MAP and abolished the increase in plasma noradrenaline and inflammation in Gαi2 ODN-infused animals on HS. Our data suggest that central Gαi2 protein prevents microglial-mediated PVN inflammation and the development of salt-sensitive hypertension.

Dataset Information

Estrogen receptor-? in the paraventricular nucleus and rostroventrolateral medulla plays an essential protective role in aldosterone/salt-induced hypertension in female rats.

Publications

Estrogen receptor-β in the paraventricular nucleus and rostroventrolateral medulla plays an essential protective role in aldosterone/salt-induced hypertension in female rats.

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