ER stress in the brain subfornical organ mediates angiotensin-dependent hypertension
Colin N. Young, … , Allyn L. Mark, Robin L. Davisson
Colin N. Young, … , Allyn L. Mark, Robin L. Davisson
Published October 15, 2012
Citation Information: J Clin Invest. 2012;122(11):3960-3964. https://doi.org/10.1172/JCI64583.
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Brief Report

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

Abstract

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.

Authors

Colin N. Young, Xian Cao, Mallikarjuna R. Guruju, Joseph P. Pierce, Donald A. Morgan, Gang Wang, Costantino Iadecola, Allyn L. Mark, Robin L. Davisson

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Figure 3

Genetic relief of ER stress selectively in the SFO prevents Ang II–induced HTN and ROS production.

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Genetic relief of ER stress selectively in the SFO prevents Ang II–induc...
An adenovirus encoding the ER molecular chaperone GRP78 was targeted to SFO 1 week prior to the start of systemic Ang II infusions. (A) Mean AP measured by radiotelemetry during Ang II infusions in conscious mice with SFO-targeted AdGRP78 or control vector AdLacZ (n = 4–5). (B) Schematic of a coronal brain section containing the SFO (lower left) and representative DHE fluorescence images of SFO from untreated mice or from mice with SFO-targeted injections of AdLacZ or AdGRP78. Summary data are shown on the bottom right (n = 4). Scale bar: 50 μm. *P < 0.05 versus day 0 or untreated; †P < 0.05 versus AdLacZ.