Endoplasmic reticulum (ER) stress mediates nuclear factor‐κ‐B (NFκB) activation in the subfornical organ (SFO) during slow‐pressor angiotensin‐II (Ang‐II) hypertension

Abstract

We recently demonstrated activation of ER stress pathways and the transcription factor NFκB in the SFO of the brain during slow‐pressor Ang‐II hypertension (HTN). Emerging evidence suggests these molecular mechanisms are closely linked. Here we tested the hypothesis that ER stress is upstream of NFκB activation in the SFO during slow‐pressor Ang‐II HTN. C57 mice underwent SFO targeted injection of an adenovirus encoding firefly luciferase downstream of NFκB response elements along with installation of an intracerebroventricular (ICV) cannula. After recovery, osmominipumps were implanted for infusion of slow‐pressor Ang‐II (600 ng/kg/min). NFκB activity was monitored in vivo by daily bioluminescence imaging during concomitant ICV administration of the chemical ER stress inhibitor TUDCA or vehicle (Veh). NFκB activity in the SFO increased gradually during Ang‐II infusion, with a pre‐hypertensive surge at day 5. This response was significantly reduced by ICV TUDCA (Veh 119744 ± 27568 vs. TUDCA 57312 ± 8164 photons/s; n=8–9, p<0.05). In line with these findings, acute induction of ER stress, via ICV administration of the chemical ER stress inducer thapsigargin (TG; 1ug), caused a robust increase in SFO‐NFκB activity (Veh Δ11919 ± 4501 vs. TG Δ194445 ± 46882 photons/s; n=4–5, p<0.05). These findings suggest that ER stress is upstream of NFκB activation in the SFO during slow‐pressor Ang‐II HTN. HL063887, HL864624