The role of the 11 beta-hydroxysteroid dehydrogenase type 2 in human hypertension

The 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta HSDP) enzyme inact ivates 11 beta-hydroxy steroids in sodium-transporting epithelia such as th e kidney, thus protecting the non-selective mineralocorticoid receptor (MR) from occupation by cortisol in humans. Inhibition by xenobiotics such as l iquorice or mutations in the HSD1182 gene, as occur in the rare monogenic h ypertensive syndrome of apparent mineralocorticoid excess (AME), result in a compromised 11 beta HSD2 enzyme activity, which in turn leads to overstim ulation of the MR by cortisol, sodium retention, hypokalaemia, low plasma r enin and aldosterone concentrations, and hypertension. Whereas the first pa tients described with AME had a severe form of hypertension and metabolic d erangements, with an increased urinary ratio of cortisol (THF+5 alpha THF) to cortisone (THE) metabolites, more subtle effects of mild 11 beta HSD2 de ficiency on blood pressure have recently been observed. Hypertension with n o other characteristic signs of AME was found in the heterozygous father of a child with AME, and we described a girl with a homozygous gene mutation resulting in only a slightly reduced 11 beta HSD2 activity causing 'essenti al' hypertension. Thus, depending on the degree of toss of enzyme activity, 11 beta HSD2 mutations can cause a spectrum of phenotypes ranging from sev ere, life-threatening hypertension in infancy to a milder form of the disea se in adults. Patients with essential hypertension usually do not have over t signs of mineralocorticoid excess, but nevertheless show a positive corre lation between blood pressure and serum sodium levels, or a negative correl ation with potassium concentrations, suggesting a mineralocorticoid influen ce. Recent studies revealed a prolonged half-life of cortisol and an increa sed ratio of urinary cortisol to cortisone metabolites in some patients wit h essential hypertension. These abnormalities may be genetically determined . A genetic association of a HSD11B2 flanking microsatellite and hypertensi on in black patients with end-stage renal disease has been reported. A rece nt analysis of a CA-repeat allele polymorphism in unselected patients with essential hypertension did not find a correlation between this marker and b lood pressure. Since steroid hormones with mineralocorticoid action modulat e renal sodium retention, one might hypothesize that genetic impairment of 11 beta HSD2 activity would be more prevalent in salt-sensitive as compared with salt-resistant subjects. Accordingly, we found a significant associat ion between the polymorphic CA-microsatellite marker and salt-sensitivity. Moreover, the mean ratio of urinary cortisol to cortisone metabolites, as a measure for 11 beta HSD2 activity, was markedly elevated in salt-sensitive subjects. These findings suggest that variants of the HSD11B2 gene may con tribute to the enhanced blood pressure response to salt in some humans. J H ypertens 2000, 18:241-248 (C) Lippincott Williams & Wilkins.