title: Brain endoplasmic reticulum stress mechanistically distinguishes the saline-intake and hypertensive response to deoxycorticosterone acetate-salt.
abstract: Endoplasmic reticulum stress has become an important mechanism in hypertension. We examined the role of endoplasmic reticulum stress in mediating the increased saline-intake and hypertensive effects in response to deoxycorticosterone acetate (DOCA)-salt. Intracerebroventricular delivery of the endoplasmic reticulum stress-reducing chemical chaperone tauroursodeoxycholic acid did not affect the magnitude of hypertension, but markedly decreased saline-intake in response to DOCA-salt. Increased saline-intake returned after tauroursodeoxycholic acid was terminated. Decreased saline-intake was also observed after intracerebroventricular infusion of 4-phenylbutyrate, another chemical chaperone. Immunoreactivity to CCAAT homologous binding protein, a marker of irremediable endoplasmic reticulum stress, was increased in the subfornical organ and supraoptic nucleus of DOCA-salt mice, but the signal was absent in control and CCAAT homologous binding protein-deficient mice. Electron microscopy revealed abnormalities in endoplasmic reticulum structure (decrease in membrane length, swollen membranes, and decreased ribosome numbers) in the subfornical organ consistent with endoplasmic reticulum stress. Subfornical organ-targeted adenoviral delivery of GRP78, a resident endoplasmic reticulum chaperone, decreased DOCA-salt-induced saline-intake. The increase in saline-intake in response to DOCA-salt was blunted in CCAAT homologous binding protein-deficient mice, but these mice exhibited a normal hypertensive response. We conclude that (1) brain endoplasmic reticulum stress mediates the saline-intake, but not blood pressure response to DOCA-salt, (2) DOCA-salt causes endoplasmic reticulum stress in the subfornical organ, which when attenuated by GRP78 blunts saline-intake, and (3) CCAAT homologous binding protein may play a functional role in DOCA-salt-induced saline-intake. The results suggest a mechanistic distinction between the importance of endoplasmic reticulum stress in mediating effects of DOCA-salt on saline-intake and blood pressure.
authors.affiliation: From the Department of Pharmacology (F.J., H.J., A.M.H., J.L.G., C.D.S.), Department of Anatomy and Cell Biology (A.P.T., M.D.C., D.T.R.), and UIHC Center for Hypertension Research (J.L.G., C.D.S.), Roy J. and Lucille Carver College of Medicine, University of Iowa; Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY (R.L.D.); and Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY (R.L.D.).
authors.forename: Fusakazu
authors.initials: F
authors.lastname: Jo
authors.affiliation: From the Department of Pharmacology (F.J., H.J., A.M.H., J.L.G., C.D.S.), Department of Anatomy and Cell Biology (A.P.T., M.D.C., D.T.R.), and UIHC Center for Hypertension Research (J.L.G., C.D.S.), Roy J. and Lucille Carver College of Medicine, University of Iowa; Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY (R.L.D.); and Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY (R.L.D.).
authors.forename: Hiromi
authors.initials: H
authors.lastname: Jo
authors.affiliation: From the Department of Pharmacology (F.J., H.J., A.M.H., J.L.G., C.D.S.), Department of Anatomy and Cell Biology (A.P.T., M.D.C., D.T.R.), and UIHC Center for Hypertension Research (J.L.G., C.D.S.), Roy J. and Lucille Carver College of Medicine, University of Iowa; Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY (R.L.D.); and Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY (R.L.D.).
authors.forename: Aline M
authors.initials: AM
authors.lastname: Hilzendeger
authors.affiliation: From the Department of Pharmacology (F.J., H.J., A.M.H., J.L.G., C.D.S.), Department of Anatomy and Cell Biology (A.P.T., M.D.C., D.T.R.), and UIHC Center for Hypertension Research (J.L.G., C.D.S.), Roy J. and Lucille Carver College of Medicine, University of Iowa; Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY (R.L.D.); and Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY (R.L.D.).
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Thompson
authors.affiliation: From the Department of Pharmacology (F.J., H.J., A.M.H., J.L.G., C.D.S.), Department of Anatomy and Cell Biology (A.P.T., M.D.C., D.T.R.), and UIHC Center for Hypertension Research (J.L.G., C.D.S.), Roy J. and Lucille Carver College of Medicine, University of Iowa; Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY (R.L.D.); and Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY (R.L.D.).
authors.forename: Martin D
authors.initials: MD
authors.lastname: Cassell
authors.affiliation: From the Department of Pharmacology (F.J., H.J., A.M.H., J.L.G., C.D.S.), Department of Anatomy and Cell Biology (A.P.T., M.D.C., D.T.R.), and UIHC Center for Hypertension Research (J.L.G., C.D.S.), Roy J. and Lucille Carver College of Medicine, University of Iowa; Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY (R.L.D.); and Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY (R.L.D.).
authors.forename: D Thomas
authors.initials: DT
authors.lastname: Rutkowski
authors.affiliation: From the Department of Pharmacology (F.J., H.J., A.M.H., J.L.G., C.D.S.), Department of Anatomy and Cell Biology (A.P.T., M.D.C., D.T.R.), and UIHC Center for Hypertension Research (J.L.G., C.D.S.), Roy J. and Lucille Carver College of Medicine, University of Iowa; Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY (R.L.D.); and Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY (R.L.D.).
authors.forename: Robin L
authors.initials: RL
authors.lastname: Davisson
authors.affiliation: From the Department of Pharmacology (F.J., H.J., A.M.H., J.L.G., C.D.S.), Department of Anatomy and Cell Biology (A.P.T., M.D.C., D.T.R.), and UIHC Center for Hypertension Research (J.L.G., C.D.S.), Roy J. and Lucille Carver College of Medicine, University of Iowa; Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY (R.L.D.); and Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY (R.L.D.).
authors.forename: Justin L
authors.initials: JL
authors.lastname: Grobe
authors.affiliation: From the Department of Pharmacology (F.J., H.J., A.M.H., J.L.G., C.D.S.), Department of Anatomy and Cell Biology (A.P.T., M.D.C., D.T.R.), and UIHC Center for Hypertension Research (J.L.G., C.D.S.), Roy J. and Lucille Carver College of Medicine, University of Iowa; Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY (R.L.D.); and Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY (R.L.D.). curt-sigmund@uiowa.edu.
authors.forename: Curt D
authors.initials: CD
authors.lastname: Sigmund
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D064791:Desoxycorticosterone Acetate / Q000494:pharmacology*; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology; D006973:Hypertension / Q000503:physiopathology*; D057967:Infusions, Intraventricular; D051379:Mice; D008810:Mice, Inbred C57BL; D011897:Random Allocation; D012016:Reference Values; D012680:Sensitivity and Specificity; D012965:Sodium Chloride / Q000378:metabolism / Q000494:pharmacology*; D018709:Statistics, Nonparametric; D013356:Subfornical Organ / Q000187:drug effects / Q000503:physiopathology
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D012965:Sodium Chloride; D064791:Desoxycorticosterone Acetate
keywords: endoplasmic reticulum stress; subfornical organ