The role of 11β-hydroxysteroid dehydrogenase type 2 in human hypertension

Abstract

Cortisol and aldosterone have the same in vitro affinity for the mineralocorticoid receptor (MR), although in vivo only aldosterone acts as a physiologic agonist of the MR, despite circulating levels of cortisol in humans and corticosterone in rodents being three orders of magnitude higher than aldosterone levels. In mineralocorticoid target organs the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) inactivates 11-hydroxy steroids, to their inactive keto-forms, thus protecting the nonselective MR from activation by glucocorticoids. The gene is highly expressed in all sodium-transporting epithelia, particularly in the kidney and colon, but also in human placenta and vascular wall. Mutations in the HSD11B2 gene cause a rare monogenic juvenile hypertensive syndrome called apparent mineralocorticoid excess (AME). In AME, compromised 11βHSD2 enzyme activity results in activation of the MR by cortisol, causing sodium retention, hypokalaemia, and salt-dependent hypertension. Whereas mutations or inhibition of 11βHSD2 by licorice have been clearly shown to produce a congenital or acquired syndrome of mineralocorticoid excess, the questions remaining are the extent to which subtle abnormalities in MR/11βHSD2 mechanisms may contribute to essential hypertension. Studies in patients with essential hypertension showed a prolonged half-life of cortisol and an increased ratio of urinary cortisol to cortisone metabolites, suggesting a deficient 11βHSD2 activity. These abnormalities may be genetically determined, as suggested by the association of a microsatellite flanking the HSD11B2 gene with hypertension in black patients with end-stage kidney disease and with salt sensitivity of blood pressure in healthy subjects. These findings indicate that variants of the HSD11B2 gene may contribute to the enhanced blood pressure response to salt and possibly to hypertension in humans.

11β-hydroxysteroid dehydrogenase type-II activity is affected by grapefruit juice and intense muscular work

“…There is evidence suggesting a link between deficiencies in 11β-HSD2 activity and increased blood pressure in normotensive and hypertensive individuals (8,9), particularly in patients diagnosed with "apparent mineralcorticoid excess" (1,9). In our study, GFJ was associated with the inhibition of 11β-HSD2 enzyme activity but not with increased systolic or diastolic blood pressure compared to CON.…”

“…The enzymatic activity of 11β-HSD2 can be estimated using the ratios of these hormones in urine (2)(3)(4)(5) and saliva (Sal) fluids (4,6,7). Subtle deficiencies in 11β-HSD2 activity have been reported in subsets of hypertensives and normotensives (8,9), whereas more severe hypertension and hypokalemia are observed in cases of substantial or complete loss of 11β-HSD2 activity (1,9).…”

Bile acid activated receptors are targets for regulation of integrity of gastrointestinal mucosa

“…Glycyrrhizic acid, the main active ingredient of licorice root extracts [57][58][59], is a triterpenoid glycosidic saponin used as a sweetener. Glycyrrhizic acid is converted in glycyrrhetinic acid in the small intestine by the activity of the intestinal microbiota and undergoes an extensive metabolic biotransformation in the liver [57][58][59]. Thus, glycyrrhizic acid is not detectable in the blood.…”

“…Despite their beneficial effects on ulcer healing, extracts of licorice roots are known to produce severe hypertension and hypokalemia [57][58][59]. This mineralcorticoid-like syndrome is primarily caused by the inhibition of 11b-hydroxysteroid dehydrogenase, an enzyme that inactivates intracellular glucocorticoids in mineralocorticoid-responsive organs, such as the kidney, increasing relative levels of cortisol, which stimulates aldosterone receptors, leading to a functional mineralocorticoid excess [57][58][59].…”

“…This mineralcorticoid-like syndrome is primarily caused by the inhibition of 11b-hydroxysteroid dehydrogenase, an enzyme that inactivates intracellular glucocorticoids in mineralocorticoid-responsive organs, such as the kidney, increasing relative levels of cortisol, which stimulates aldosterone receptors, leading to a functional mineralocorticoid excess [57][58][59]. Our data indicate that in addition to inhibition of 11b-hydroxysteroid dehydrogenase or activation of estrogen receptors or peroxisome-proliferator-activated receptors [60], glycyrrhizic acid might also function as an FXR ligand/ modulator.…”