E. Lovati et al., Molecular basis of human salt sensitivity: The role of the 11 beta-hydroxysteroid dehydrogenase type 2, J CLIN END, 84(10), 1999, pp. 3745-3749
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.