title: Endoplasmic reticulum and oxidant stress mediate nuclear factor-κB activation in the subfornical organ during angiotensin II hypertension.
abstract: Endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) generation in the brain circumventricular subfornical organ (SFO) mediate the central hypertensive actions of Angiotensin II (ANG II). However, the downstream signaling events remain unclear. Here we tested the hypothesis that angiotensin type 1a receptors (AT1aR), ER stress, and ROS induce activation of the transcription factor nuclear factor-κB (NF-κB) during ANG II-dependent hypertension. To spatiotemporally track NF-κB activity in the SFO throughout the development of ANG II-dependent hypertension, we used SFO-targeted adenoviral delivery and longitudinal bioluminescence imaging in mice. During low-dose infusion of ANG II, bioluminescence imaging revealed a prehypertensive surge in NF-κB activity in the SFO at a time point prior to a significant rise in arterial blood pressure. SFO-targeted ablation of AT1aR, inhibition of ER stress, or adenoviral scavenging of ROS in the SFO prevented the ANG II-induced increase in SFO NF-κB. These findings highlight the utility of bioluminescence imaging to longitudinally track transcription factor activation during the development of ANG II-dependent hypertension and reveal an AT1aR-, ER stress-, and ROS-dependent prehypertensive surge in NF-κB activity in the SFO. Furthermore, the increase in NF-κB activity before a rise in arterial blood pressure suggests a causal role for SFO NF-κB in the development of ANG II-dependent hypertension.
authors.affiliation: Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York;
authors.forename: Colin N
authors.initials: CN
authors.lastname: Young
authors.affiliation: Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York;
authors.forename: Anfei
authors.initials: A
authors.lastname: Li
authors.affiliation: Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York;
authors.forename: Frederick N
authors.initials: FN
authors.lastname: Dong
authors.affiliation: Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York;
authors.forename: Julie A
authors.initials: JA
authors.lastname: Horwath
authors.affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, New York; and.
authors.forename: Catharine G
authors.initials: CG
authors.lastname: Clark
authors.affiliation: Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York; Cell and Developmental Biology, Weill Cornell Medical College, New York, New York robin.davisson@cornell.edu.
authors.forename: Robin L
authors.initials: RL
authors.lastname: Davisson
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013356:Subfornical Organ / Q000187:drug effects*
chemical_list: D016328:NF-kappa B; D017382:Reactive Oxygen Species; D000804:Angiotensin II
keywords: NF-κB, ER stress; angiotensin II; central nervous system; hypertension