title: Glucocorticoids Induce Nondipping Blood Pressure by Activating the Thiazide-Sensitive Cotransporter.
abstract: Blood pressure (BP) normally dips during sleep, and nondipping increases cardiovascular risk. Hydrochlorothiazide restores the dipping BP profile in nondipping patients, suggesting that the NaCl cotransporter, NCC, is an important determinant of daily BP variation. NCC activity in cells is regulated by the circadian transcription factor per1. In vivo, circadian genes are entrained via the hypothalamic-pituitary-adrenal axis. Here, we test whether abnormalities in the day:night variation of circulating glucocorticoid influence NCC activity and BP control. C57BL6/J mice were culled at the peak (1:00 AM) and trough (1:00 PM) of BP. We found no day:night variation in NCC mRNA or protein but NCC phosphorylation on threonine(53) (pNCC), required for NCC activation, was higher when mice were awake, as was excretion of NCC in urinary exosomes. Peak NCC activity correlated with peak expression of per2 and bmal1 (clock genes) and sgk1 and tsc22d3 (glucocorticoid-responsive kinases). Adrenalectomy reduced NCC abundance and blunted the daily variation in pNCC levels without affecting variation in clock gene transcription. Chronic corticosterone infusion increased bmal1, per1, sgk1, and tsc22d3 expression during the inactive phase. Inactive phase pNCC was also elevated by corticosterone, and a nondipping BP profile was induced. Hydrochlorothiazide restored rhythmicity of BP in corticosterone-treated mice without affecting BP in controls. Glucocorticoids influence the day:night variation in NCC activity via kinases that control phosphorylation. Abnormal glucocorticoid rhythms impair NCC and induce nondipping. Night-time dosing of thiazides may be particularly beneficial in patients with modest glucocorticoid excess.
authors.affiliation: From the The British Heart Foundation Centre for Cardiovascular Science (J.R.I., W.O., T.S.P., A.R.H., R.W.H., N.D., D.J.W., J.W.D., M.A.B.) and The Centre for Integrative Physiology (P.W.F.), The University of Edinburgh, Edinburgh, United Kingdom; and Dietetics, Nutrition, and Biological Sciences Department, Queen Margaret University, Musselburgh, United Kingdom (E.A.S.A.-D.).
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Ivy
authors.affiliation: From the The British Heart Foundation Centre for Cardiovascular Science (J.R.I., W.O., T.S.P., A.R.H., R.W.H., N.D., D.J.W., J.W.D., M.A.B.) and The Centre for Integrative Physiology (P.W.F.), The University of Edinburgh, Edinburgh, United Kingdom; and Dietetics, Nutrition, and Biological Sciences Department, Queen Margaret University, Musselburgh, United Kingdom (E.A.S.A.-D.).
authors.forename: Wilna
authors.initials: W
authors.lastname: Oosthuyzen
authors.affiliation: From the The British Heart Foundation Centre for Cardiovascular Science (J.R.I., W.O., T.S.P., A.R.H., R.W.H., N.D., D.J.W., J.W.D., M.A.B.) and The Centre for Integrative Physiology (P.W.F.), The University of Edinburgh, Edinburgh, United Kingdom; and Dietetics, Nutrition, and Biological Sciences Department, Queen Margaret University, Musselburgh, United Kingdom (E.A.S.A.-D.).
authors.forename: Theresa S
authors.initials: TS
authors.lastname: Peltz
authors.affiliation: From the The British Heart Foundation Centre for Cardiovascular Science (J.R.I., W.O., T.S.P., A.R.H., R.W.H., N.D., D.J.W., J.W.D., M.A.B.) and The Centre for Integrative Physiology (P.W.F.), The University of Edinburgh, Edinburgh, United Kingdom; and Dietetics, Nutrition, and Biological Sciences Department, Queen Margaret University, Musselburgh, United Kingdom (E.A.S.A.-D.).
authors.forename: Amelia R
authors.initials: AR
authors.lastname: Howarth
authors.affiliation: From the The British Heart Foundation Centre for Cardiovascular Science (J.R.I., W.O., T.S.P., A.R.H., R.W.H., N.D., D.J.W., J.W.D., M.A.B.) and The Centre for Integrative Physiology (P.W.F.), The University of Edinburgh, Edinburgh, United Kingdom; and Dietetics, Nutrition, and Biological Sciences Department, Queen Margaret University, Musselburgh, United Kingdom (E.A.S.A.-D.).
authors.forename: Robert W
authors.initials: RW
authors.lastname: Hunter
authors.affiliation: From the The British Heart Foundation Centre for Cardiovascular Science (J.R.I., W.O., T.S.P., A.R.H., R.W.H., N.D., D.J.W., J.W.D., M.A.B.) and The Centre for Integrative Physiology (P.W.F.), The University of Edinburgh, Edinburgh, United Kingdom; and Dietetics, Nutrition, and Biological Sciences Department, Queen Margaret University, Musselburgh, United Kingdom (E.A.S.A.-D.).
authors.forename: Neeraj
authors.initials: N
authors.lastname: Dhaun
authors.affiliation: From the The British Heart Foundation Centre for Cardiovascular Science (J.R.I., W.O., T.S.P., A.R.H., R.W.H., N.D., D.J.W., J.W.D., M.A.B.) and The Centre for Integrative Physiology (P.W.F.), The University of Edinburgh, Edinburgh, United Kingdom; and Dietetics, Nutrition, and Biological Sciences Department, Queen Margaret University, Musselburgh, United Kingdom (E.A.S.A.-D.).
authors.forename: Emad A S
authors.initials: EA
authors.lastname: Al-Dujaili
authors.affiliation: From the The British Heart Foundation Centre for Cardiovascular Science (J.R.I., W.O., T.S.P., A.R.H., R.W.H., N.D., D.J.W., J.W.D., M.A.B.) and The Centre for Integrative Physiology (P.W.F.), The University of Edinburgh, Edinburgh, United Kingdom; and Dietetics, Nutrition, and Biological Sciences Department, Queen Margaret University, Musselburgh, United Kingdom (E.A.S.A.-D.).
authors.forename: David J
authors.initials: DJ
authors.lastname: Webb
authors.affiliation: From the The British Heart Foundation Centre for Cardiovascular Science (J.R.I., W.O., T.S.P., A.R.H., R.W.H., N.D., D.J.W., J.W.D., M.A.B.) and The Centre for Integrative Physiology (P.W.F.), The University of Edinburgh, Edinburgh, United Kingdom; and Dietetics, Nutrition, and Biological Sciences Department, Queen Margaret University, Musselburgh, United Kingdom (E.A.S.A.-D.).
authors.forename: James W
authors.initials: JW
authors.lastname: Dear
authors.affiliation: From the The British Heart Foundation Centre for Cardiovascular Science (J.R.I., W.O., T.S.P., A.R.H., R.W.H., N.D., D.J.W., J.W.D., M.A.B.) and The Centre for Integrative Physiology (P.W.F.), The University of Edinburgh, Edinburgh, United Kingdom; and Dietetics, Nutrition, and Biological Sciences Department, Queen Margaret University, Musselburgh, United Kingdom (E.A.S.A.-D.).
authors.forename: Peter W
authors.initials: PW
authors.lastname: Flatman
authors.affiliation: From the The British Heart Foundation Centre for Cardiovascular Science (J.R.I., W.O., T.S.P., A.R.H., R.W.H., N.D., D.J.W., J.W.D., M.A.B.) and The Centre for Integrative Physiology (P.W.F.), The University of Edinburgh, Edinburgh, United Kingdom; and Dietetics, Nutrition, and Biological Sciences Department, Queen Margaret University, Musselburgh, United Kingdom (E.A.S.A.-D.). Matthew.Bailey@ed.ac.uk.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Bailey
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001795:Blood Pressure Determination; D002940:Circadian Rhythm / Q000187:drug effects*; D003345:Corticosterone / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D006852:Hydrochlorothiazide / Q000494:pharmacology*; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology*; D015151:Immunoblotting; D007262:Infusions, Intravenous; D007677:Kidney Function Tests; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D016133:Polymerase Chain Reaction / Q000379:methods; D011897:Random Allocation; D012680:Sensitivity and Specificity; D064486:Solute Carrier Family 12, Member 3 / Q000235:genetics / Q000378:metabolism*; D027981:Symporters / Q000378:metabolism
chemical_list: D064486:Solute Carrier Family 12, Member 3; D027981:Symporters; D006852:Hydrochlorothiazide; D003345:Corticosterone
keywords: cardiovascular disease; circadian rhythm; diabetes mellitus; hypertension; risk factors