title: Conditional Deletion of Hsd11b2 in the Brain Causes Salt Appetite and Hypertension.
abstract: BACKGROUND
  The hypertensive syndrome of Apparent Mineralocorticoid Excess is caused by loss-of-function mutations in the gene encoding 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2), allowing inappropriate activation of the mineralocorticoid receptor by endogenous glucocorticoid. Hypertension is attributed to sodium retention in the distal nephron, but 11βHSD2 is also expressed in the brain. However, the central contribution to Apparent Mineralocorticoid Excess and other hypertensive states is often overlooked and is unresolved. We therefore used a Cre-Lox strategy to generate 11βHSD2 brain-specific knockout (Hsd11b2.BKO) mice, measuring blood pressure and salt appetite in adults.
  
  
  RESULTS
  Basal blood pressure, electrolytes, and circulating corticosteroids were unaffected in Hsd11b2.BKO mice. When offered saline to drink, Hsd11b2.BKO mice consumed 3 times more sodium than controls and became hypertensive. Salt appetite was inhibited by spironolactone. Control mice fed the same daily sodium intake remained normotensive, showing the intrinsic salt resistance of the background strain. Dexamethasone suppressed endogenous glucocorticoid and abolished the salt-induced blood pressure differential between genotypes. Salt sensitivity in Hsd11b2.BKO mice was not caused by impaired renal sodium excretion or volume expansion; pressor responses to phenylephrine were enhanced and baroreflexes impaired in these animals.
  
  
  CONCLUSIONS
  Reduced 11βHSD2 activity in the brain does not intrinsically cause hypertension, but it promotes a hunger for salt and a transition from salt resistance to salt sensitivity. Our data suggest that 11βHSD2-positive neurons integrate salt appetite and the blood pressure response to dietary sodium through a mineralocorticoid receptor-dependent pathway. Therefore, central mineralocorticoid receptor antagonism could increase compliance to low-sodium regimens and help blood pressure management in cardiovascular disease.
authors.affiliation: From British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, United Kingdom (L.C.E., J.R.I., C.W., J.A.M., R.I.M., T.H.C., C.J.K., J.J.M., J.R.S., M.C.H., M.A.B.); and Dietetics, Nutrition and Biological Sciences Department, Queen Margaret University, Edinburgh, United Kingdom (E.A.S.Al-D.). The current address for Dr Evans is Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee; the current address for Dr Wyrwoll is School of Anatomy, Physiology & Human Biology, The University of Western Australia, Crawley, Australia; and the current address for Dr Christensen is Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense.
authors.forename: Louise C
authors.initials: LC
authors.lastname: Evans
authors.affiliation: From British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, United Kingdom (L.C.E., J.R.I., C.W., J.A.M., R.I.M., T.H.C., C.J.K., J.J.M., J.R.S., M.C.H., M.A.B.); and Dietetics, Nutrition and Biological Sciences Department, Queen Margaret University, Edinburgh, United Kingdom (E.A.S.Al-D.). The current address for Dr Evans is Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee; the current address for Dr Wyrwoll is School of Anatomy, Physiology & Human Biology, The University of Western Australia, Crawley, Australia; and the current address for Dr Christensen is Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Ivy
authors.affiliation: From British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, United Kingdom (L.C.E., J.R.I., C.W., J.A.M., R.I.M., T.H.C., C.J.K., J.J.M., J.R.S., M.C.H., M.A.B.); and Dietetics, Nutrition and Biological Sciences Department, Queen Margaret University, Edinburgh, United Kingdom (E.A.S.Al-D.). The current address for Dr Evans is Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee; the current address for Dr Wyrwoll is School of Anatomy, Physiology & Human Biology, The University of Western Australia, Crawley, Australia; and the current address for Dr Christensen is Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Wyrwoll
authors.affiliation: From British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, United Kingdom (L.C.E., J.R.I., C.W., J.A.M., R.I.M., T.H.C., C.J.K., J.J.M., J.R.S., M.C.H., M.A.B.); and Dietetics, Nutrition and Biological Sciences Department, Queen Margaret University, Edinburgh, United Kingdom (E.A.S.Al-D.). The current address for Dr Evans is Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee; the current address for Dr Wyrwoll is School of Anatomy, Physiology & Human Biology, The University of Western Australia, Crawley, Australia; and the current address for Dr Christensen is Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense.
authors.forename: Julie A
authors.initials: JA
authors.lastname: McNairn
authors.affiliation: From British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, United Kingdom (L.C.E., J.R.I., C.W., J.A.M., R.I.M., T.H.C., C.J.K., J.J.M., J.R.S., M.C.H., M.A.B.); and Dietetics, Nutrition and Biological Sciences Department, Queen Margaret University, Edinburgh, United Kingdom (E.A.S.Al-D.). The current address for Dr Evans is Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee; the current address for Dr Wyrwoll is School of Anatomy, Physiology & Human Biology, The University of Western Australia, Crawley, Australia; and the current address for Dr Christensen is Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense.
authors.forename: Robert I
authors.initials: RI
authors.lastname: Menzies
authors.affiliation: From British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, United Kingdom (L.C.E., J.R.I., C.W., J.A.M., R.I.M., T.H.C., C.J.K., J.J.M., J.R.S., M.C.H., M.A.B.); and Dietetics, Nutrition and Biological Sciences Department, Queen Margaret University, Edinburgh, United Kingdom (E.A.S.Al-D.). The current address for Dr Evans is Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee; the current address for Dr Wyrwoll is School of Anatomy, Physiology & Human Biology, The University of Western Australia, Crawley, Australia; and the current address for Dr Christensen is Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense.
authors.forename: Thorbjørn H
authors.initials: TH
authors.lastname: Christensen
authors.affiliation: From British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, United Kingdom (L.C.E., J.R.I., C.W., J.A.M., R.I.M., T.H.C., C.J.K., J.J.M., J.R.S., M.C.H., M.A.B.); and Dietetics, Nutrition and Biological Sciences Department, Queen Margaret University, Edinburgh, United Kingdom (E.A.S.Al-D.). The current address for Dr Evans is Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee; the current address for Dr Wyrwoll is School of Anatomy, Physiology & Human Biology, The University of Western Australia, Crawley, Australia; and the current address for Dr Christensen is Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense.
authors.forename: Emad A S
authors.initials: EA
authors.lastname: Al-Dujaili
authors.affiliation: From British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, United Kingdom (L.C.E., J.R.I., C.W., J.A.M., R.I.M., T.H.C., C.J.K., J.J.M., J.R.S., M.C.H., M.A.B.); and Dietetics, Nutrition and Biological Sciences Department, Queen Margaret University, Edinburgh, United Kingdom (E.A.S.Al-D.). The current address for Dr Evans is Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee; the current address for Dr Wyrwoll is School of Anatomy, Physiology & Human Biology, The University of Western Australia, Crawley, Australia; and the current address for Dr Christensen is Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kenyon
authors.affiliation: From British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, United Kingdom (L.C.E., J.R.I., C.W., J.A.M., R.I.M., T.H.C., C.J.K., J.J.M., J.R.S., M.C.H., M.A.B.); and Dietetics, Nutrition and Biological Sciences Department, Queen Margaret University, Edinburgh, United Kingdom (E.A.S.Al-D.). The current address for Dr Evans is Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee; the current address for Dr Wyrwoll is School of Anatomy, Physiology & Human Biology, The University of Western Australia, Crawley, Australia; and the current address for Dr Christensen is Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense.
authors.forename: John J
authors.initials: JJ
authors.lastname: Mullins
authors.affiliation: From British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, United Kingdom (L.C.E., J.R.I., C.W., J.A.M., R.I.M., T.H.C., C.J.K., J.J.M., J.R.S., M.C.H., M.A.B.); and Dietetics, Nutrition and Biological Sciences Department, Queen Margaret University, Edinburgh, United Kingdom (E.A.S.Al-D.). The current address for Dr Evans is Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee; the current address for Dr Wyrwoll is School of Anatomy, Physiology & Human Biology, The University of Western Australia, Crawley, Australia; and the current address for Dr Christensen is Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Seckl
authors.affiliation: From British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, United Kingdom (L.C.E., J.R.I., C.W., J.A.M., R.I.M., T.H.C., C.J.K., J.J.M., J.R.S., M.C.H., M.A.B.); and Dietetics, Nutrition and Biological Sciences Department, Queen Margaret University, Edinburgh, United Kingdom (E.A.S.Al-D.). The current address for Dr Evans is Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee; the current address for Dr Wyrwoll is School of Anatomy, Physiology & Human Biology, The University of Western Australia, Crawley, Australia; and the current address for Dr Christensen is Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense.
authors.forename: Megan C
authors.initials: MC
authors.lastname: Holmes
authors.affiliation: From British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, United Kingdom (L.C.E., J.R.I., C.W., J.A.M., R.I.M., T.H.C., C.J.K., J.J.M., J.R.S., M.C.H., M.A.B.); and Dietetics, Nutrition and Biological Sciences Department, Queen Margaret University, Edinburgh, United Kingdom (E.A.S.Al-D.). The current address for Dr Evans is Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee; the current address for Dr Wyrwoll is School of Anatomy, Physiology & Human Biology, The University of Western Australia, Crawley, Australia; and the current address for Dr Christensen is Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense. Matthew.Bailey@ed.ac.uk.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Bailey
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D017704:Baroreflex / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D066249:Craving / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology; D004327:Drinking Behavior; D005813:Genes, Synthetic; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043204:Mineralocorticoid Excess Syndrome, Apparent / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D000451:Mineralocorticoid Receptor Antagonists / Q000627:therapeutic use; D009399:Nephrons / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D064231:Nestin / Q000235:genetics; D009474:Neurons / Q000502:physiology; D011188:Potassium / Q000652:urine; D012333:RNA, Messenger / Q000096:biosynthesis; D018161:Receptors, Mineralocorticoid / Q000502:physiology*; D012021:Reflex, Abnormal; D017673:Sodium Chloride, Dietary / Q000633:toxicity*; D017552:Solitary Nucleus / Q000201:enzymology* / Q000503:physiopathology; D013148:Spironolactone / Q000494:pharmacology
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D009419:Nerve Tissue Proteins; C577486:Nes protein, rat; D064231:Nestin; D012333:RNA, Messenger; D018161:Receptors, Mineralocorticoid; D017673:Sodium Chloride, Dietary; D013148:Spironolactone; D003907:Dexamethasone; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C000609895:HSD11B2 protein, mouse; D011188:Potassium; D003345:Corticosterone
keywords: aldosterone; mineralocorticoids; pressoreceptors; salt; solitary nucleus