Molecular inhibition of endoplasmic reticulum (ER) stress targeted to the subfornical organ (SFO) prevents slow‐pressor angiotensin‐II (Ang‐II) mediated hypertension

Abstract

We have shown that ICV administration of the chemical ER stress inhibitor TUDCA ameliorates slow‐pressor Ang‐II hypertension (HTN); however the precise brain nuclei involved are unknown. Since the SFO is critical in this model of HTN, we tested the hypothesis that ER stress in SFO is causally linked to Ang‐II HTN. A new adenovirus encoding the ER chaperone GRP78 was constructed (AdGRP78) in order to inhibit ER stress site‐selectively in the SFO. In vitro studies in Neuro2A cells confirmed AdGRP78 was targeted to ER and inhibited Ang‐II‐induced ER stress biomarker induction. In vivo targeting of AdGRP78 to SFO of C57 mice caused robust SFO‐selective expression of the GRP78 transgene and inhibition of the ER stress biomarker CHOP in this region following ICV injection of the chemical ER stress inducer thapsigargin (1ug; AdLacZ 1.6 ± 0.1 vs AdGRP78 1.1 ± 0.1, p<0.05). To test if AdGRP78‐mediated inhibition of ER stress in SFO prevents slow‐pressor Ang‐II HTN, mice underwent SFO‐targeted injection of AdGRP78 or AdLacZ and were instrumented with radiotelemeters (DSI) for mean arterial blood pressure (MAP) recordings. After recovery, osmominipumps were implanted for 2 wk slow‐pressor Ang‐II infusion. AdGRP78 prevented the development of slow‐pressor Ang‐II HTN (day 14 MAP: AdLacZ 138 ± 3 vs AdGRP78 106 ± 3 mmHg, p<0.05, n=4–6). These data implicate ER stress in the SFO as a key mediator of slow‐pressor Ang‐II HTN.HL063887