Abstract 176: Role of Endoplasmic Reticulum Stress in the SFO in Fluid Balance and Metabolic Effects of Brain Renin-Angiotensin System Activation

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Abstract

Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have been identified as important contributors to neurological diseases and have been implicated in mediating hypothalamic inflammation and the hypertensive response to angiotensin II. We examined the role of ER stress and the UPR in the metabolic and fluid balance effects of brain angiotensin in two mouse models: 1) “sRA” transgenic mice (expressing human renin in neurons via the synapsin promoter crossed with human angiotensinogen via its own promoter), and 2) DOCA-salt treated C57BL/6J mice. Both DOCA-salt and sRA mice exhibit hyperactivity of the brain RAS, suppression of circulating RAS, hypertension, polydipsia, and an elevated resting metabolic rate. We examined the accumulation of UPR biomarker CCAAT-enhancer-binding protein homologous protein (CHOP) by immunocytochemistry in the brain of both models. CHOP is considered a marker of chronic ER stress. Increased CHOP immunoreactivity was evident in the subfornical organ (SFO) of sRA mice but was absent in non-transgenic (NT) and CHOP-/- mice. There was also increased CHOP immunoreactivity in the SFO of DOCA-salt mice compared with untreated controls. Next, we infused the ER stress-reducing chemical chaperone tauroursodeoxycholic acid (TUDCA, 5.28 ug/day, or aCSF vehicle) to assess if ER stress is mechanistically related to the hypertension, polydipsia, and elevated resting metabolic rate observed in both models. ICV TUDCA (3-5 day pretreatment then continuously for 3 wks) significantly attenuated the polydipsia (aCSF 20.7±0.9 vs TUDCA 10.8±1.0 mL/day, P<0.05) and metabolic rate (aCSF, 3.38±0.07 vs TUDCA 3.16±0.06 mL O2/100g/min, P<0.05) in the DOCA-salt model. ICV TUDCA (3 wks) had similar effects on the polydipsia in the sRA model (51±10% of aCSF control, P<0.05). DOCA-salt caused (P<0.05) increases in 24 hr mean arterial pressure (MAP) that were unaffected by ICV TUDCA (aCSF baseline 114±3 to 128±4 mmHg with DOCA-salt; TUDCA 117±7 to 129±4). Heart rate responses to DOCA-salt were attenuated (P<0.05) with ICV TUDCA (aCSF baseline 528±10 to 448±15 BPM with DOCA-salt; TUDCA 529±6 to 486±11). Together these data mechanistically implicate ER stress in the fluid and metabolic responses to increased brain RAS activity.

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