11beta-HSD2 protects the mineralocorticoid receptor from cortisol excess; mutations in the HSD11B2 gene explain an inherited form of hypertension, the syndrome of 'apparent mineralocorticoid excess', in which 'Cushing's disease of the kidney' results in cortisol-mediated mineralocorticoid excess.
AME represents a spectrum of mineralocorticoid hypertension with severity reflecting the underlying genetic defect in the 11beta-HSD2; although AME is a genetic disorder, several exogenous compounds can bring about the symptoms by inhibiting 11beta-HSD2 enzyme.
AME represents a spectrum of mineralocorticoid hypertension with severity reflecting the underlying genetic defect in the 11beta-HSD2 gene; classification into distinct subtypes is inappropriate.
Apparent mineralocorticoid excess (AME) is a rare autosomal recessive genetic disorder causing severe hypertension in childhood due to a deficiency of 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2), which is encoded by HSD11B2.
Because hypertension in Black people tends to be of the low-renin, salt sensitive type, we genotyped independent sets of hypertensives of Afro-American (59 kindreds) and Afro-Caribbean (66 kindreds) origin using a highly polymorphic (heterozygosity index 0.84) CA repeat polymorphism in the first intron of HSD11B2.
Because polymorphisms in HSD11B2 have been associated with hypertension and salt sensitivity, we characterized the human VPATPD gene.It spans 19 kb and consists of 8 exons.
Because the hypertension associated with AME is of the salt-sensitive type, it seemed possible that decreases in 11-HSD2 activity might be associated with salt sensitivity.
Epidemiological data suggests that polymorphic variability in the HSD11B2 gene determines salt sensitivity in the general population, which is a key predisposing factor to adult onset hypertension in some patients.
Furthermore, in the rat, an association between placental 11 beta HSD activity and the subsequent development of hypertension in the offspring has been reported.
Furthermore, polymorphisms in the 11β-HSD2 coding gene (HSD11B2) have been linked to high blood pressure and salt sensitivity, major cardiovascular risk factors.
Impaired 11beta-HSD2 activity has been suggested in patients with hypertension as well as in patients with renal disease, where it may contribute to sodium retention, oedema and hypertension.
Impaired 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2)-dependent cortisol inactivation can lead to electrolyte dysbalance, hypertension and cardiometabolic disease.
In AME, defective HSD11B2 enzyme activity results in overstimulation of the mineralocorticoid receptor (MR) by cortisol, causing sodium retention, hypokalemia, and salt-dependent hypertension.
In congenital 11beta-HSD deficiency and after administration of 11beta-HSD inhibitors, suppression of 11beta-HSD2 activity in the kidney has been believed to cause renal mineralocorticoid excess, resulting in sodium retention and hypertension.
In the development of diabetes-induced hypertension, the effect of spironolactone on mean systolic blood pressure may be associated with the mineralocorticoid effects of corticosterone on renal MR, as well as an alteration of renal 11beta-HSD2 activity and its mRNA expression in insulin-dependent diabetic rats.