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 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.
Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853-6401, USA.
Colin N
CN
Young
Xian
X
Cao
Mallikarjuna R
MR
Guruju
Joseph P
JP
Pierce
Donald A
DA
Morgan
Gang
G
Wang
Costantino
C
Iadecola
Allyn L
AL
Mark
Robin L
RL
Davisson
D000804:Angiotensin II / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002756:Cholagogues and Choleretics / Q000494:pharmacology; D002908:Chronic Disease; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D006360:Heat-Shock Proteins / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D013356:Subfornical Organ / Q000378:metabolism / Q000473:pathology; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000009:adverse effects* / Q000494:pharmacology
D002756:Cholagogues and Choleretics; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine