Molecular basis of human salt sensitivity: The role of the 11 beta-hydroxysteroid dehydrogenase type 2

Salt-sensitive subjects (SS) increase their blood pressure with increasing salt intake. Because steroid hormones modulate renal sodium retention, we h ypothesize that the activity of the 11 beta-hydroxy steroid dehydrogenase t ype 2 (11 beta HSD2) enzyme is impaired in SS subjects as compared with sal t-resistant (SR) subjects. The 11 beta HSD2 enzyme inactivates 11-hydroxy s teroids in the kidney, thus protecting the nonselective mineralocorticoid r eceptor from occupation by glucocorticoids. We performed an association stu dy using a recently identified single AluI polymorphism in exon 3 and a pol ymorphic microsatellite marker of the HSD11B2 gene in 149 normotensive whit e males (37 SS and 112 SR). The activity of the enzyme 11 beta HSD2 was ass essed by determining the urinary ratio of cortisol (THF+5 alpha THF) to cor tisone (THE) metabolites by gas chromatography in all the 37 SS subjects an d in 37 age- and body habitus-matched SR volunteers. Mean (THF+5 alpha THF) /THE ratio was markedly elevated in SS subjects compared with SR subjects ( 1.51 +/- 0.34 vs. 1.08 +/- 026, P < 0.00001), indicating enhanced access of glucocorticoids to the mineralocorticoid receptor in SS subjects. In 58% o f SS subjects this ratio was higher than the maximum levels in SR subjects. The salt-induced elevation in arterial pressure increased with,increasing (THF+5 alpha TKF)/THE ratio (r(2) = 0.51, P < 0.0001). A total of 12 allele s of the polymorphic microsatellite marker were detected. Homozygosity for the allele A7 was higher in SS subjects than in SR subjects (41 us. 28%, P < 0.005), whereas the occurrence of the allele A7 with allele A8 was lower in SS subjects than in SR subjects (8 us. 15%, P < 0.03). The prevalence of salt sensitivity was 35% in subjects with allele A7/A7, whereas salt sensi tivity was present in only 9% of the subjects with allele A7/A8. The (THF+5 alpha THF)/THE ratio was higher in subjects homozygous for the A7 microsat ellite allele as compared with the corresponding control subjects. The prev alence of the AluI allele was 8.0% in SR subjects and 5.4% in SS subjects a nd did not correlate with blood pressure. The decreased activity of the 11 beta HSD2 in SS subjects indicates that this enzyme is involved in salt-sen sitive blood pressure response in humans. The association of a polymorphic microsatellite marker of the gene with a reduced 11 beta HSD2 activity sugg ests that variants of the HSD11B2 gene contribute to enhanced blood pressur e response to salt in humans.