Relief of endoplasmic reticulum stress in the brain rescues high fat diet‐induced hypertension but this is not due to the subfornical organ (682.3)

Abstract

We have recently demonstrated robust ER stress in central neural cardioregulatory regions of HFD animals, with particularly prominent elevations in the SFO. In line with this, global relief of brain ER stress via intracerebroventricular delivery of the chemical ER chaperone TUDCA ameliorates HFD‐induced hypertension (Δ‐6±1 mmHg, p<0.05). However, the precise neural regions involved remain unknown. We hypothesized that ER stress in the SFO mediates obesity‐induced hypertension. HFD (n=13; 20 wks) and age‐matched normal chow (n=10) fed C57Bl/6 mice were instrumented with radiotelemeters for mean arterial pressure (MAP) measurements and underwent SFO‐targeted microinjections of an adenovirus encoding the ER chaperone GRP78 (AdGRP78) to reduce ER stress. Relative to normal chow, HFD control vector treated mice demonstrated a significant increase in MAP (102±3 vs 116±1 mmHg, normal chow vs HFD, p<0.05). SFO‐targeted AdGRP78 did not influence the HFD‐induced increase in MAP (118±1 mmHg, HFD AdGRP78, p>0.05). Analysis of ER stress biomarkers revealed that AdGRP78 selectively reduced ER stress within the SFO, but not other neural regions (e.g. p58IPK mRNA SFO: 1.0±0.1 vs 0.6±0.1, HFD AdLacZ vs HFD AdGRP78, p<0.05). These findings suggest that, while brain ER stress contributes to HFD‐induced hypertension, ER stress in the SFO does not appear to be involved in the maintenance of obesity‐mediated hypertension.Grant Funding Source: Supported by HL63887, HL96571, HL84207, AHA13POST14410020, K99HL166776