Expression of renal 11β-hydroxysteroid dehydrogenase type 2 is decreased in patients with impaired renal function

Abstract

Objective: Renal 11b-hydroxysteroid dehydrogenase type 2 (11b-HSD2) enables selective access of aldosterone to the mineralocorticoid receptor (MR). Impaired 11b-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. To date, these studies have relied upon urinary cortisol (F) metabolite levels as surrogate markers of renal 11b-HSD2 activity. Methods: We have directly analysed renal 11b-HSD2 mRNA expression in 95 patients undergoing kidney biopsy using TaqMan real-time PCR. Serum and 24-h urine samples were used to document underlying renal function and endocrine parameters. Urinary F and cortisone (E) metabolites were analysed using gas chromatography/mass spectrometry. Results: Expression of 11b-HSD2 did not correlate with blood pressure or urinary Na/K ratio, but a significant positive correlation with creatinine clearance was observed (r ¼ 0.284; P , 0.01). Immunofluorescence and confocal laser microscopy confirmed decreased 11b-HSD2 expression in patients with impaired renal function. For the first time, we showed that 11b-HSD2 mRNA expression correlated negatively with the urinary free (UF) F/E (UFF/UFE) ratio (r ¼ 0.276; P , 0.05) as well as with the urinary tetrahydrocortisol þ 5a-tetrahydrocortisol/tetrahydrocortisone ((THF þ aTHF)/THE) ratio (r ¼ 0.256; P , 0.05). No difference in 11b-HSD2 mRNA expression or in the UFF/UFE ratio was found between groups with no proteinuria, microalbuminuria, moderate or severe proteinuria. In contrast, the urinary (THF þ aTHF)/THE ratio increased significantly (P , 0.05) in patients with severe albuminuria, suggesting increased hepatic 11b-HSD1 in those patients. Conclusions: These data suggest that renal 11b-HSD2 expression may be represented only marginally better, if at all, by the UFF/UFE than by the (THF þ aTHF)/THE ratio. Reduced renal 11b-HSD2 expression may lead to occupancy of the MR by glucocorticoids such as cortisol and may contribute to the increased sodium retention seen in patients with impaired renal function.European Journal of Endocrinology 153 291-299

Sexual dimorphism in cortisol secretion starts after age 10 in healthy children: urinary cortisol metabolite excretion rates during growth

“…Additionally, administration of isotope-labeled tracers might influence endogenous cortisol production by negative feedback (18). However, it has been shown that determination of urinary excretion rates of the major endogenous glucocorticoid metabolites presents a suitable alternative to isotopic methods for the determination of cortisol secretion (15,19,50) and gas chromatography-mass spectrometry (GC-MS) urinary steroid profiling has been successfully used in determining cortisol secretion in preterm infants (14).Meanwhile, measurement of urinary 24-h major cortisol metabolites is an established method used by numerous endocrine research groups (9,16,23,29,39,41,43,49) to examine adrenocortical activity and/or glucocorticoid metabolism in healthy and ill children and adults. This relies on the fact that the sum of the seven major urinary cortisol metabolites (for details see SUBJECTS AND METHODS) encompasses almost 80% of the cortisol secreted per day by the adrenal gland (27,40).…”

Regulation of 11<i>β</i>-Hydroxysteroid Dehydrogenase Type 1 and 2 in Rheumatoid Arthritis

“…Importantly correlations between the ratios of cortisol to cortisone metabolites, (THF + 5aTHF/THE) and F/E as index markers of the activities of 11β-HSD1 and 2, respectively, [22,23], and various clinical and laboratory parameters of disease activity were found (Figures 3 and 4). These correlations present evidence, that the enzyme activities are regulated by the disease activity (Figures 3 and 4).…”

Role of 11β-hydroxysteroid dehydrogenase 2 renal activity in potassium homeostasis in rats with chronic renal failure

“…Impaired activity of this isozyme has been demonstrated in hypoxia (19) and in renal disease (20,21), syndromes that develop with abnormal handling of potassium and sodium and high blood pressure. These observations led us to hypothesize that the decreased 11β-HSD2 may improve the access of glucocorticoids to mineralocorticoid receptors, leading to hypertension and Na + retention.…”