HSD11B2 CA-repeat and sodium balance

Abstract

Type 2 11β-hydroxysteroid dehydrogenase encoded by the HSD11B2 gene converts cortisol to inactive cortisone and thus protects the mineralocorticoid receptor from cortisol exposure. Impaired activity of this enzyme leads to mineralocorticoid excess, suggesting HSD11B2 as a candidate locus for patients at risk of developing low renin or salt-sensitive essential hypertension. In the present study, we searched for frequent polymorphisms in 155 Japanese subjects but detected none in the proximal promoter or coding regions of HSD11B2. Following this result, we genotyped a highly polymorphic CA-repeat polymorphism within the first intron in 848 normotensive and 430 hypertensive Japanese patients, and we then analyzed its association with disease and clinical parameters. We confirmed 12 alleles (12, 15-25 CA repeats) in the population and found no significant difference in the distribution of the allele length between normotensive and hypertensive patients. In 174 normal subjects without medication, urinary cortisol excretion was higher in subjects with more CA repeats in the shorter allele, but the ratio of urinary cortisone to cortisol, a reliable marker of renal HSD11B2 activity, did not differ. However, longer CA-repeat length was positively correlated with 24-h urinary sodium excretion, fractional sodium excretion and potassium clearance, and this observation was confirmed when the longer CA-repeat length was dichotomized. Thus, HSD11B2 CA-repeat genotype is not associated with hypertension itself, but with renal sodium excretion, probably through salt intake/appetite.

Conditional Deletion of Hsd11b2 in the Brain Causes Salt Appetite and Hypertension

“…Studies in humans suggest that 11βHSD2 in the brain may contribute to abnormal sodium homeostasis: increased salt appetite has been reported in AME 15 and loss-of-function variants positively associate with sodium intake in the general population. 16 Moreover, the sympathetic nervous system is activated in Hsd11b2 null mice, contributing importantly to the maintenance of hypertension in these animals. 11…”

Alterations of Cortisol Metabolism in Human Disorders

“…In a large Japanese study, there was no significant difference in the distribution of the allele length between normotensive and hypertensive patients, or associations with urinary steroid ratios, but longer CA-repeat length was positively correlated with 24-h urinary sodium excretion. The authors suggested that HSD11B2 CA-repeat genotype was not associated with hypertension itself, but with renal sodium excretion, possibly by regulating salt intake/appetite [72]. Taken together, the results are tantalizing but inconclusive with regard to the effect of CA repeat length on the in vivo expression of 11-HSD2.…”

11β‐Hydroxysteroid dehydrogenase and the brain: Not (yet) lost in translation

“…The effects are reversed by MR antagonism or suppression of endogenous corticosterone [69]. Intriguingly, a longer HSD11B2 intronic CA repeat linked to modestly reduced enzyme activity associates with higher salt intake without changes in renal glucocorticoid metabolism [70], implying brain 11β‐HSD2 influences salt appetite in humans. There is an opportunity for elegant human experimental medicine studies.…”