Role of the 11β-hydroxysteroid dehydrogenase type 2 in blood pressure regulation

The renal 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta HSD2) enzyme inactivates 11-hydroxy steroids in the kidney, thus protecting the nonselective mineralocorticoid receptor (MR) from occupation by glucocorticoids. The gene is highly expressed in all sodium-transporting epithelia, bur also in human placenta, pancreas, and thyroid. Mutations in the HSD11B2 gene cause a rare monogenic juvenile hypertensive syndrome called apparent mineralocorticoid excess (AME). In AME, compromised 11 beta HSD2 enzyme activity results in overstimulation of the MR by cortisol, causing sodium retention, hypokalemia, and salt-dependent hypertension. Re cent evidence suggests a role of the 11 beta HSD2 in essential hypertension. We found hypertension with no other characteristic signs of AME in the heterozygous father of a child with AME and in a girl with a homozygous gene mutation resulting in a mild deficiency of 11 beta HSD2. Moreover, some studies in patients with essential hypertension showed a prolonged half-life of cortisol and an increased ratio of urinary cortisol to cortisone metabolites. suggesting a deficient 11 beta HSD2 activity. These abnormalities may be genetically determined. A genetic association of a microsatellite flanking the HSD11B2 gene and hypertension in black patients with end-stage renal disease has been reported. We recently analyzed a CA-repeal allele polymorphism in unselected patients with essential hypertension, but did not find any correlation between this marker and blood pressure. However, we did find an association between this polymorphic CA microsatellite marker and salt sensitivity. Moreover, the activity of the 11 beta HSD2, as shown by elevated mean ratios of urinary cortisol to cortisone metabolites. was decreased in salt-sensitive compared with salt-resistant subjects. These findings indicate that variants of the HSD11B2 gene contribute to the enhanced blood pressure response to salt in humans.