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.

Redox-Sensitive Endoplasmic Reticulum Stress and Autophagy at Rostral Ventrolateral Medulla Contribute to Hypertension in Spontaneously Hypertensive Rats

“…This finding is also at variance with a recent report, 39 in which tissue-specific supplement of GRP78 in the subfornical organ with adenoval vector encoding GRP78 prevents the development of hypertension induced by peripheral Ang II. Apart from its beneficial functions of abrogating ER stress, 39,50 GRP78 is reported recently as an obligatory component of ER stress-induced autophagy. 24 Gene knockdown of GRP78 has been demonstrated to block ER stress-induced autophagosome formation in human cells.…”

“…41 As such, alterations of the cellular redox environment either in the direction of oxidization or reduction would affect protein processing, resulting in the induction of ER stress. 41 The notion that redox-sensitive ER stress is present in RVLM is at variance with a recent study, 39 which shows that ER stress is the source of oxidative stress in the subfornical organ in mediating Ang II-induced hypertension. Because ER stress and oxidative stress are tightly coupled mechanisms, 34 it is conceivable that a vicious cycle orchestrated by reciprocal interactions between ER stress and oxidative stress may play a key role in neural mechanisms of chronic hypertension.…”

“…The site specificity of ER stress at RVLM in the manifestation of hypertension is confirmed by observations that microinjection of tunicamycin to areas outside the confines of RVLM did not affect MAP in normotensive WKY rats. We noted that methods used for quantitative analysis of eIF2α phosphorylation are controversial; both SDS-PAGE 38 and Phos-tag gel 39 have been reported in the literature. Thus, we included analysis by Phos-tag gels in the present study to validate the results obtained from the conventional SDS-PAGE used in Western blot analysis.…”

“…We further reason that, under normotensive conditions, GRP78 supplement is required to sustain the beneficial UPR that prevents cells from exhibiting chronic ER stress and the associated hypertension. 39 An emerging proposition from these narratives is that depending on the degree and duration of ER stress, GRP78 might play a double-edge sword role in ER stress-associated cellular responses. At an early stage of ER stress, GRP78 may act as a chaperone to abrogate ER stress.…”

“…Nonetheless, the jury is still out with regard to the precise interplay between the 2 cellular processes. Speculatively, ER stress is known to initiate ROS production and redox deviation, 39,55 and oxidative stress may initiate ER stress through protein oxidative modification. 41 In addition, whether this interplay between oxidative stress and ER stress takes place in other brain areas that subserve central cardiovascular regulation also warrants investigation.…”