Abstract 083: Role of Endoplasmic Reticulum Stress in the Subfornical Organ (SFO) in Fluid Balance and Metabolic Effects of Brain Renin-Angiotensin System (RAS) Activation

Endoplasmic reticulum (ER) stress has been identified as an important contributor to neurological diseases and implicated in mediating hypothalamic inflammation and the hypertensive effects of angiotensin II (AngII). We examined the role of ER stress in the metabolic and fluid balance effects of brain AngII in two mouse models: 1) sRA transgenic mice (expressing human renin in neurons and human angiotensinogen in glia and neurons), 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 (RMR). CCAAT-enhancer-binding protein homologous protein (CHOP), a marker of chronic ER stress, was examined by immunocytochemistry in the brain of both models. CHOP immunoreactivity was evident in the SFO of sRA and DOCA-salt mice but was absent in control and CHOP-/- mice. 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 RMR observed in both models. In initial studies, ICV TUDCA significantly attenuated the polydipsia (aCSF 20.7±0.9 vs TUDCA 10.8±1.0 mL/day, n=6,2) and RMR (aCSF, 3.38±0.07 vs TUDCA 3.16±0.06 mL O2/100g/min, P<0.05 n=13,11) 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 n=3,4). In the DOCA-salt model, daily ICV injections of TUDCA (10 days, 5ug/ul) markedly reduced drinking, but polydipsia returned one day after the injections were terminated (n=14,12). Daily ICV injection of another ER stress reducer 4-phenylbutyrate (5ug/ul) also reduced drinking (P<0.05 n=5,4). To assess the functional role of CHOP, we measured RMR and water intake in CHOP-/- mice. Interestingly, CHOP-/- mice exhibited increased baseline RMR (CHOP-/- 0.161±0.010 vs C57 0.140±0.005 kcal/hr, P<0.05 n=10,9). The increase in water intake in response to DOCA-salt was blunted (32.7±0.5 vs 22.8±1.1 ml/day, P<0.05, n=4,5) in CHOP-/- mice. Together these data mechanistically implicate ER stress in the fluid and metabolic responses to increased brain RAS activity and suggest CHOP may play a functional role.