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ER stress in the brain subfornical organ mediates angiotensin-dependent hypertension

Although endoplasmic reticulum (ER) stress is a pathologic mechanism in a variety of chronic diseases, it is unclear what role it plays in chronic hypertension (HTN). Dysregulation of brain mechanisms controlling arterial pressure is strongly implicated in HTN, particularly in models involving angio...

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Published in:The Journal of clinical investigation 2012-11, Vol.122 (11), p.3960-3964
Main Authors: Young, Colin N, Cao, Xian, Guruju, Mallikarjuna R, Pierce, Joseph P, Morgan, Donald A, Wang, Gang, Iadecola, Costantino, Mark, Allyn L, Davisson, Robin L
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creator Young, Colin N
Cao, Xian
Guruju, Mallikarjuna R
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Davisson, Robin L
description Although endoplasmic reticulum (ER) stress is a pathologic mechanism in a variety of chronic diseases, it is unclear what role it plays in chronic hypertension (HTN). Dysregulation of brain mechanisms controlling arterial pressure is strongly implicated in HTN, particularly in models involving angiotensin II (Ang II). We tested the hypothesis that ER stress in the brain is causally linked to Ang II-dependent HTN. Chronic systemic infusion of low-dose Ang II in C57BL/6 mice induced slowly developing HTN, which was abolished by co-infusion of the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) into the lateral cerebroventricle. Investigations of the brain regions involved revealed robust increases in ER stress biomarkers and profound ER morphological abnormalities in the circumventricular subfornical organ (SFO), a region outside the blood-brain barrier and replete with Ang II receptors. Ang II-induced HTN could be prevented in this model by selective genetic supplementation of the ER chaperone 78-kDa glucose-regulated protein (GRP78) in the SFO. These data demonstrate that Ang II-dependent HTN is mediated by ER stress in the brain, particularly the SFO. To our knowledge, this is the first report that ER stress, notably brain ER stress, plays a key role in chronic HTN. Taken together, these findings may have broad implications for the pathophysiology of this disease.
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subjects Analysis
Angiotensin
Angiotensin II - adverse effects
Angiotensin II - pharmacology
Animals
Biomedical research
Brain - metabolism
Brain - pathology
Brief Report
Care and treatment
Cholagogues and Choleretics - pharmacology
Chronic Disease
Chronic illnesses
Diagnosis
Endoplasmic reticulum
Endoplasmic Reticulum Stress
Health aspects
Heat-Shock Proteins - metabolism
Homeostasis
Hypertension
Hypertension - chemically induced
Hypertension - metabolism
Hypertension - pathology
Hypotheses
Kinases
Mice
Nervous system
Physiological aspects
Protein synthesis
Proteins
Stress (Physiology)
Subfornical Organ - metabolism
Subfornical Organ - pathology
Taurochenodeoxycholic Acid - pharmacology
Vasoconstrictor Agents - adverse effects
Vasoconstrictor Agents - pharmacology
title ER stress in the brain subfornical organ mediates angiotensin-dependent hypertension
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