Genetic knockdown of estrogen receptor-alpha in the subfornical organ augments ANG II-induced hypertension in female mice

Baojian Xue, Zhongming Zhang, Terry G. Beltz, Fang Guo, Meredith Hay, Alan Kim Johnson

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

The present study tested the hypotheses that 1) ERα in the brain plays a key role in the estrogen-protective effects against ANG II-induced hypertension, and 2) that the subfornical organ (SFO) is a key site where ERα mediates these protective actions. In this study, a “floxed” ERα transgenic mouse line (ERα<sup>flox</sup>) was used to create models in which ERα was knocked down in the brain or just in the SFO. Female mice with ERα ablated in the nervous system (Nestin-ERα<sup>–</sup> mice) showed greater increases in blood pressure (BP) in response to ANG II. Furthermore, females with ERα knockdown specifically in the SFO [SFO adenovirus-Cre (Ad-Cre) injected ERα<sup>flox</sup> mice] also showed an enhanced pressor response to ANG II. Immunohistochemical (IHC), RT-PCR, and Western blot analyses revealed a marked reduction in the expression of ERα in nervous tissues and, in particular, in the SFO. These changes were not present in peripheral tissues in Nestin- ERα<sup>–</sup> mice or Ad-Cre-injected ERα<sup>flox</sup> mice. mRNA expression of components of the renin-angiotensin system in the lamina terminalis were upregulated in Nestin-ERα<sup>–</sup> mice. Moreover, ganglionic blockade on day 7 after ANG II infusions resulted in a greater reduction of BP in Nestin-ERα<sup>–</sup> mice or SFO Ad-Cre-injected mice, suggesting that knockdown of ERα in the nervous system or the SFO alone augments central ANG II-induced increase in sympathetic tone. The results indicate that interfering with the action of estrogen on SFO ERα is sufficient to abolish the protective effects of estrogen against ANG II-induced hypertension.

Original languageEnglish (US)
Pages (from-to)R507-R516
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume308
Issue number6
DOIs
StatePublished - Mar 15 2015

Fingerprint

Subfornical Organ
Estrogen Receptor alpha
Hypertension
Nestin
Adenoviridae
Estrogens
Nervous System
Blood Pressure
Nerve Tissue
Brain
Renin-Angiotensin System
Transgenic Mice
Hypothalamus
Western Blotting
Polymerase Chain Reaction
Messenger RNA

Keywords

  • ANG II
  • Blood pressure
  • Estrogen receptor-α
  • Nervous system
  • Subfornical organ

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Genetic knockdown of estrogen receptor-alpha in the subfornical organ augments ANG II-induced hypertension in female mice. / Xue, Baojian; Zhang, Zhongming; Beltz, Terry G.; Guo, Fang; Hay, Meredith; Johnson, Alan Kim.

In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology, Vol. 308, No. 6, 15.03.2015, p. R507-R516.

Research output: Contribution to journalArticle

@article{8ed79ef842ca43baaf19d8dbb8748966,
title = "Genetic knockdown of estrogen receptor-alpha in the subfornical organ augments ANG II-induced hypertension in female mice",
abstract = "The present study tested the hypotheses that 1) ERα in the brain plays a key role in the estrogen-protective effects against ANG II-induced hypertension, and 2) that the subfornical organ (SFO) is a key site where ERα mediates these protective actions. In this study, a “floxed” ERα transgenic mouse line (ERαflox) was used to create models in which ERα was knocked down in the brain or just in the SFO. Female mice with ERα ablated in the nervous system (Nestin-ERα– mice) showed greater increases in blood pressure (BP) in response to ANG II. Furthermore, females with ERα knockdown specifically in the SFO [SFO adenovirus-Cre (Ad-Cre) injected ERαflox mice] also showed an enhanced pressor response to ANG II. Immunohistochemical (IHC), RT-PCR, and Western blot analyses revealed a marked reduction in the expression of ERα in nervous tissues and, in particular, in the SFO. These changes were not present in peripheral tissues in Nestin- ERα– mice or Ad-Cre-injected ERαflox mice. mRNA expression of components of the renin-angiotensin system in the lamina terminalis were upregulated in Nestin-ERα– mice. Moreover, ganglionic blockade on day 7 after ANG II infusions resulted in a greater reduction of BP in Nestin-ERα– mice or SFO Ad-Cre-injected mice, suggesting that knockdown of ERα in the nervous system or the SFO alone augments central ANG II-induced increase in sympathetic tone. The results indicate that interfering with the action of estrogen on SFO ERα is sufficient to abolish the protective effects of estrogen against ANG II-induced hypertension.",
keywords = "ANG II, Blood pressure, Estrogen receptor-α, Nervous system, Subfornical organ",
author = "Baojian Xue and Zhongming Zhang and Beltz, {Terry G.} and Fang Guo and Meredith Hay and Johnson, {Alan Kim}",
year = "2015",
month = "3",
day = "15",
doi = "10.1152/ajpregu.00406.2014",
language = "English (US)",
volume = "308",
pages = "R507--R516",
journal = "American Journal of Physiology",
issn = "0363-6143",
publisher = "American Physiological Society",
number = "6",

}

TY - JOUR

T1 - Genetic knockdown of estrogen receptor-alpha in the subfornical organ augments ANG II-induced hypertension in female mice

AU - Xue, Baojian

AU - Zhang, Zhongming

AU - Beltz, Terry G.

AU - Guo, Fang

AU - Hay, Meredith

AU - Johnson, Alan Kim

PY - 2015/3/15

Y1 - 2015/3/15

N2 - The present study tested the hypotheses that 1) ERα in the brain plays a key role in the estrogen-protective effects against ANG II-induced hypertension, and 2) that the subfornical organ (SFO) is a key site where ERα mediates these protective actions. In this study, a “floxed” ERα transgenic mouse line (ERαflox) was used to create models in which ERα was knocked down in the brain or just in the SFO. Female mice with ERα ablated in the nervous system (Nestin-ERα– mice) showed greater increases in blood pressure (BP) in response to ANG II. Furthermore, females with ERα knockdown specifically in the SFO [SFO adenovirus-Cre (Ad-Cre) injected ERαflox mice] also showed an enhanced pressor response to ANG II. Immunohistochemical (IHC), RT-PCR, and Western blot analyses revealed a marked reduction in the expression of ERα in nervous tissues and, in particular, in the SFO. These changes were not present in peripheral tissues in Nestin- ERα– mice or Ad-Cre-injected ERαflox mice. mRNA expression of components of the renin-angiotensin system in the lamina terminalis were upregulated in Nestin-ERα– mice. Moreover, ganglionic blockade on day 7 after ANG II infusions resulted in a greater reduction of BP in Nestin-ERα– mice or SFO Ad-Cre-injected mice, suggesting that knockdown of ERα in the nervous system or the SFO alone augments central ANG II-induced increase in sympathetic tone. The results indicate that interfering with the action of estrogen on SFO ERα is sufficient to abolish the protective effects of estrogen against ANG II-induced hypertension.

AB - The present study tested the hypotheses that 1) ERα in the brain plays a key role in the estrogen-protective effects against ANG II-induced hypertension, and 2) that the subfornical organ (SFO) is a key site where ERα mediates these protective actions. In this study, a “floxed” ERα transgenic mouse line (ERαflox) was used to create models in which ERα was knocked down in the brain or just in the SFO. Female mice with ERα ablated in the nervous system (Nestin-ERα– mice) showed greater increases in blood pressure (BP) in response to ANG II. Furthermore, females with ERα knockdown specifically in the SFO [SFO adenovirus-Cre (Ad-Cre) injected ERαflox mice] also showed an enhanced pressor response to ANG II. Immunohistochemical (IHC), RT-PCR, and Western blot analyses revealed a marked reduction in the expression of ERα in nervous tissues and, in particular, in the SFO. These changes were not present in peripheral tissues in Nestin- ERα– mice or Ad-Cre-injected ERαflox mice. mRNA expression of components of the renin-angiotensin system in the lamina terminalis were upregulated in Nestin-ERα– mice. Moreover, ganglionic blockade on day 7 after ANG II infusions resulted in a greater reduction of BP in Nestin-ERα– mice or SFO Ad-Cre-injected mice, suggesting that knockdown of ERα in the nervous system or the SFO alone augments central ANG II-induced increase in sympathetic tone. The results indicate that interfering with the action of estrogen on SFO ERα is sufficient to abolish the protective effects of estrogen against ANG II-induced hypertension.

KW - ANG II

KW - Blood pressure

KW - Estrogen receptor-α

KW - Nervous system

KW - Subfornical organ

UR - http://www.scopus.com/inward/record.url?scp=84930852374&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84930852374&partnerID=8YFLogxK

U2 - 10.1152/ajpregu.00406.2014

DO - 10.1152/ajpregu.00406.2014

M3 - Article

C2 - 25552661

AN - SCOPUS:84930852374

VL - 308

SP - R507-R516

JO - American Journal of Physiology

JF - American Journal of Physiology

SN - 0363-6143

IS - 6

ER -