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Endoplasmic reticulum stress is upstream of angiotensin‐II (Ang‐II)‐induced reactive oxygen species (ROS) formation in the subfornical organ (SFO)
Author(s) -
Young Colin N.,
Wang Gang,
Iadecola Costantino,
Mark Allyn L.,
Davisson Robin L.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.906.15
Subject(s) - endoplasmic reticulum , oxidative stress , unfolded protein response , reactive oxygen species , angiotensin ii , tauroursodeoxycholic acid , endocrinology , medicine , chemistry , subfornical organ , receptor , biochemistry
We have demonstrated that oxidative stress and endoplasmic reticulum (ER) stress in the brain SFO mediate Ang‐II‐dependent hypertension (HTN). Whether these two mechanisms are linked remains unknown. Here we tested the hypothesis that ER stress mediates Ang‐II‐induced oxidative stress in the SFO. First, freshly dissociated murine SFO cells were treated with Ang‐II in the presence or absence of the chemical ER stress inhibitor TUDCA. Dihyroethidium (DHE) was used as the ROS indicator. Ang‐II caused a significant increase in ROS production in SFO cells and this response was abrogated by pretreatment with TUDCA (1.28±0.04 vs 1.00±0.01 fold vehicle, Ang‐II vs Ang‐II + TUDCA, p<0.05). Second, C57Bl/6 mice underwent SFO‐targeted microinjections of an adenovirus encoding the ER chaperone GRP78 (AdGRP78, n=4), an approach we have shown to reduce ER stress and prevent Ang‐II HTN. SFO‐targeted AdLacZ (n=4) served as a control. Following recovery, mice were implanted with osmominpumps for 2 wk delivery of low‐dose Ang‐II. Ang‐II caused a significant increase in DHE fluorescence in the SFO at 14 days of Ang‐II infusion. This increase in ROS formation was prevented by SFO‐selective reduction in ER stress using AdGRP78 (1.78±0.21 vs 1.02±0.03 fold untreated, AdLacZ vs AdGRP78, p<0.05). These findings demonstrate that Ang‐II‐induced ER stress is a source of SFO oxidative stress in this model of HTN. HL63887, HL96571, HL84207