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Abstract 409: Endoplasmic Reticulum Stress Mediates Fluid Balance and Metabolic Effects of the Brain Renin-Angiotensin System


 Endoplasmic reticulum (ER) stress and the subsequent unfolded protein response (UPR) have been identified as important contributors to various neural diseases. We examined the role of ER stress and the UPR in the metabolic and fluid balance effects of brain angiotensin in two mouse models. The ER stress-reducing chemical chaperone tauroursodeoxycholic acid (TUDCA, 5.28 ug/day) or aCSF vehicle was infused into the lateral cerebral ventricle (ICV) of either C57Bl/6J mice treated for three weeks with high dietary sodium and chronic subcutaneous deoxycorticosterone acetate (the “DOCA-salt” model), or transgenic “sRA” mice that express human renin in neurons via the synapsin promoter and human angiotensinogen via its own promoter. Both the DOCA-salt and sRA models exhibit hyperactivity of the brain RAS, suppression of circulating RAS, hypertension, polydipsia, and an elevated resting metabolic rate. Forebrain, midbrain, and hindbrain regions of sRA mice exhibited a significant elevation of CHOP mRNA, a marker of long-term UPR. There were no changes in CHOP expression in the cortex and cerebellum. ICV TUDCA significantly attenuated the polydipsia (DOCA-aCSF 20.7±0.9 vs DOCA-TUDCA 10.8±1.0 mL/day, P<0.05) and metabolic rate (DOCA-aCSF, 3.38±0.07 vs DOCA-TUDCA 3.16±0.06 mL O
 2
 /100g/min, P<0.05) in the DOCA-salt model. ICV TUDCA had similar effects on the polydipsia in the sRA model (51±10% of aCSF control, P<0.05). Metabolic studies in the sRA model, and blood pressure in the sRA and DOCA models are ongoing. Together these data mechanistically implicate ER stress in the fluid and metabolic responses to increased brain RAS activity.
