11beta-hydroxysteroid dehydrogenase and its role in the syndrome of apparent mineralocorticoid excess.
Aldosterone, the most important mineralocorticoid, regulates electrolyte excretion and intravascular volume mainly through its effects on renal cortical collecting ducts, where it acts to increase sodium resorption from and potassium excretion into the urine. Excess secretion of aldosterone or other mineralocorticoids, or abnormal sensitivity to mineralocorticoids, may result in hypokalemia, suppressed plasma renin activity, and hypertension. The syndrome of apparent mineralocorticoid excess (AME) is an inherited form of hypertension in which 11beta-hydroxysteroid dehydrogenase (11-HSD) is defective. This enzyme converts cortisol to its inactive metabolite, cortisone. Because mineralocorticoid receptors themselves have similar affinities for cortisol and aldosterone, it is hypothesized that the deficiency allows these receptors to be occupied by cortisol, which normally circulates at levels far higher than those of aldosterone. We cloned cDNA and genes encoding two isozymes of 11-HSD. The liver or 11-HSD1 isozyme has relatively low affinity for steroids, is expressed at high levels in the liver but poorly in the kidney, and is not defective in AME. The kidney or 11-HSD2 isozyme has high steroid affinity and is expressed at high levels in the kidney and placenta. Mutations in the gene for the latter isozyme have been detected in all kindreds with AME. Moreover, the in vitro enzymatic activity conferred by each mutation is strongly correlated with the ratio of cortisone to cortisol metabolites in the urine, with age of diagnosis, and with birth weight. This suggests that the biochemical and clinical phenotype of AME is largely determined by genotype.
White
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PC
Department of Pediatrics, University of Texas Southwestern Medical Center, 75390-9063, USA. perrin.white@utsouthwestern.edu
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D002648:Child; D005260:Female; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000172:deficiency* / Q000235:genetics; D006929:Hyperaldosteronism / Q000453:epidemiology / Q000209:etiology*; D006973:Hypertension / Q000453:epidemiology / Q000209:etiology*; D007008:Hypokalemia / Q000453:epidemiology / Q000209:etiology*; D012083:Renin / Q000097:blood*; D013577:Syndrome
D006913:Hydroxysteroid Dehydrogenases; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C468387:HSD11B2 protein, human; D012083:Renin