title: Mineralocorticoid Excess or Glucocorticoid Insufficiency: Renal and Metabolic Phenotypes in a Rat Hsd11b2 Knockout Model.
abstract: Obesity and hypertension are 2 major health issues of the 21st century. The syndrome of apparent mineralocorticoid excess is caused by deficiency of 11β-hydroxysteroid dehydrogenase type 2 (Hsd11b2), which normally inactivates glucocorticoids, rendering the mineralocorticoid receptor aldosterone-specific. The metabolic consequences of Hsd11b2 knockout in the rat are investigated in parallel with electrolyte homeostasis. Hsd11b2 was knocked out, by pronuclear microinjection of targeted zinc-finger nuclease mRNAs, and 1 line was characterized for its response to renal and metabolic challenges. Plasma 11-dehydrocorticosterone was below detection thresholds, and Hsd11b2 protein was undetected by Western blot, indicating complete ablation. Homozygotes were 13% smaller than wild-type littermates, and were polydipsic and polyuric. Their kidneys, adrenals, and hearts were significantly enlarged, but mesenteric fat pads and liver were significantly smaller. On a 0.3% Na diet, mean arterial blood pressure was ≈65 mm Hg higher than controls but only 25 mm Hg higher on a 0.03% Na(+) diet. Urinary Na/K ratio of homozygotes was similar to controls on 0.3% Na(+) diet but urinary albumin and calcium were elevated. Corticosterone and aldosterone levels showed normal circadian variation on both a 0.3% and 0.03% Na(+) diet, but plasma renin was suppressed in homozygotes on both diets. Plasma glucose responses to an oral glucose challenge were reduced despite low circulating insulin, indicating much greater sensitivity to insulin in homozygotes. The rat model reveals mechanisms linking electrolyte homeostasis and metabolic control through the restriction of Hsd11b1 substrate availability.
authors.affiliation: From the Molecular Physiology Laboratory, University of Edinburgh/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, Edinburgh, United Kingdom. Linda.mullins@ed.ac.uk.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Mullins
authors.affiliation: From the Molecular Physiology Laboratory, University of Edinburgh/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kenyon
authors.affiliation: From the Molecular Physiology Laboratory, University of Edinburgh/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Bailey
authors.affiliation: From the Molecular Physiology Laboratory, University of Edinburgh/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: Bryan R
authors.initials: BR
authors.lastname: Conway
authors.affiliation: From the Molecular Physiology Laboratory, University of Edinburgh/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Diaz
authors.affiliation: From the Molecular Physiology Laboratory, University of Edinburgh/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: John J
authors.initials: JJ
authors.lastname: Mullins
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics* / Q000378:metabolism; D000311:Adrenal Glands / Q000378:metabolism / Q000473:pathology*; D000450:Aldosterone / Q000097:blood*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000235:genetics; D003345:Corticosterone / Q000031:analogs & derivatives* / Q000097:blood; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D009929:Organ Size / Q000235:genetics; D010641:Phenotype; D051381:Rats; D055647:Rats, Transgenic; D012083:Renin / Q000097:blood
chemical_list: D001786:Blood Glucose; D000450:Aldosterone; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D012083:Renin; C003552:11-dehydrocorticosterone; D003345:Corticosterone
keywords: knockout rat; mineralocorticoid excess syndrome, apparent; rat Hsd11b1 protein; rat Hsd11b2 protein; zinc-finger nuclease