Expression of renal 11beta-hydroxysteroid dehydrogenase type 2 is decreased in patients with impaired renal function.
OBJECTIVE
Renal 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) enables selective access of aldosterone to the mineralocorticoid receptor (MR). 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. To date, these studies have relied upon urinary cortisol (F) metabolite levels as surrogate markers of renal 11beta-HSD2 activity.


METHODS
We have directly analysed renal 11beta-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 11beta-HSD2 did not correlate with blood pressure or urinary Na/K ratio, but a significant positive correlation with creatinine clearance was observed (r = 0.284; P < 0.01). Immunofluorescence and confocal laser microscopy confirmed decreased 11beta-HSD2 expression in patients with impaired renal function. For the first time, we showed that 11beta-HSD2 mRNA expression correlated negatively with the urinary free (UF) F/E (UFF/UFE) ratio (r = 0.276; P < 0.05) as well as with the urinary tetrahydrocortisol + 5alpha-tetrahydrocortisol/tetrahydrocortisone ((THF + alphaTHF)/THE) ratio (r = 0.256; P < 0.05). No difference in 11beta-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 + alphaTHF)/THE ratio increased significantly (P < 0.05) in patients with severe albuminuria, suggesting increased hepatic 11beta-HSD1 in those patients.


CONCLUSIONS
These data suggest that renal 11beta-HSD2 expression may be represented only marginally better, if at all, by the UFF/UFE than by the (THF + alphaTHF)/THE ratio. Reduced renal 11beta-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.
Quinkler
Marcus
M
Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, UK.
Zehnder
Daniel
D
Lepenies
Julia
J
Petrelli
Massimiliano D
MD
Moore
Jasbir S
JS
Hughes
Susan V
SV
Cockwell
Paul
P
Hewison
Martin
M
Stewart
Paul M
PM
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics* / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000419:Albuminuria / Q000378:metabolism / Q000473:pathology; D001706:Biopsy; D003404:Creatinine / Q000652:urine; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006854:Hydrocortisone / Q000652:urine; D007668:Kidney / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D051437:Renal Insufficiency / Q000378:metabolism* / Q000473:pathology; D012964:Sodium / Q000378:metabolism; D013760:Tetrahydrocortisol / Q000652:urine
D012333:RNA, Messenger; D018161:Receptors, Mineralocorticoid; D013760:Tetrahydrocortisol; D012964:Sodium; D003404:Creatinine; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D006854:Hydrocortisone