Endoplasmic reticulum stress and hypertension — a new paradigm?
Alyssa H. Hasty, David G. Harrison
Alyssa H. Hasty, David G. Harrison
Published October 15, 2012
Citation Information: J Clin Invest. 2012;122(11):3859-3861. https://doi.org/10.1172/JCI65173.
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Endoplasmic reticulum stress and hypertension — a new paradigm?

Abstract

Hypertension occurs in approximately 30% of individuals in Western populations and is known to be a major cause of stroke, heart failure, and myocardial infarction. Despite this, the molecular etiology of hypertension remains poorly understood. In this issue of the JCI, Young et al. show that endoplasmic reticulum (ER) stress is an essential signaling event for angiotensin II–induced hypertension in cells of the central nervous system. This provides new insight into the molecular mechanisms that drive hypertension and suggests a potential target for future therapy.

Authors

Alyssa H. Hasty, David G. Harrison

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Figure 1

Role of central nervous system ER stress in hypertension.

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Role of central nervous system ER stress in hypertension. Angiotensin II...
Angiotensin II acts on the circumventricular organs, including the subfornical organ (SFO), the organum vasculosum of the lamina terminalis (OVLT), the median eminence (ME), and the area postrema (AP). Also shown for orientation are the median preoptic nucleus (MnPO), the rostral ventral lateral medulla (RVLM), and the nucleus tractus solitarius (NTS). SON, supraoptic nucleus. In the SFO, angiotensin II promotes ER stress, documented by distension and disorganization of ER cisternae, increased inhibitor of interferon-induced and double-stranded RNA-activated protein kinase (p58IPK), increased C/EBP homologous protein (CHOP), and phosphorylation of PKR-like endoplasmic reticulum kinase (PERK). ER stress causes dissociation of 78 kDa glucose-regulated protein (GRP78) from PERK, inositol requiring protein (IRE-1), and activating reticulum factor-6 (ATF-6). Ultimately, ER stress in the SFO leads to increased sympathetic outflow and hypertension. Local administration of thapsigargin (TG), which also promotes ER stress, mimics these effects. Treatment with the chemical chaperone tauroursodeoxycholic acid (TUDCA) or overexpression of GRP78 prevents ER stress in the SFO and abrogates angiotensin II–induced hypertension.