Reduced activity of
11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) plays a role in
essential hypertension and the sensitivity of blood pressure to dietary
salt. Nonconservative mutations in the coding region are extremely rare and do not explain the variable
11beta-HSD2 activity. We focused therefore on the 5'-regulatory region and identified and characterized the first promoter polymorphisms. Transfections of variants G-209A and G-126A into SW620 cells reduced promoter activity and affinity for activators
nuclear factor 1 (NF1) and Sp1.
Chromatin immunoprecipitation revealed Sp1, NF1, and
glucocorticoid receptor (GR) binding to the HSD11B2 promoter.
Dexamethasone induced expression of
mRNA and activity of HSD11B2. GR and/or NF1 overexpression increased endogenous HSD11B2
mRNA and activity. GR complexes cooperated with NF1 to activate HSD11B2, an effect diminished in the presence of the G-209A variant. When compared to
salt-resistant subjects (96),
salt-sensitive volunteers (54) more frequently had the G-209A variant, higher occurrence of alleles A4/A7 of polymorphic microsatellite marker, and higher urinary ratios of
cortisol to
cortisone metabolites. First, we conclude that the mechanism of
glucocorticoid-induced HSD11B2 expression is mainly mediated by cooperation between GR and NF1 on the HSD11B2 promoter and, second, that the newly identified promoter variants reduce activity and cooperation of cognate
transcription factors, resulting in diminished HSD11B2 transcription, an effect favoring
salt sensitivity.