Regulation of 11β-hydroxysteroid dehydrogenase type 2 by diuretics and the renin–angiotensin–aldosterone axis

In the kidney and colon 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) inactivates cortisol to cortisone, thereby protecting the non-selective mineralocorticoid receptor from cortisol. Deficiency of 11β-HSD2 results in cortisol-mediated sodium retention and hypertension, suggesting that the physiological regulation of 11β-HSD2 in mineralocorticoid target tissues may be important in modulating sodium homoeostasis and blood pressure control. Using the human epithelial colon cell line SW-620, reverse transcriptase-polymerase chain reaction and enzyme kinetic analysis indicated expression of only 11β-HSD2 (K_m for cortisol 66 nmol/l). Bradykinin (10^-8 to 10^-12 mol/l), frusemide (10^-4 to 10^-9 mol/l), benzamiloride hydrochloride (10^-5 to 10^-10 mol/l) and atrial natriuretic peptide (10^-6 to 10^-10 mol/l) had no effect on 11β-HSD2 expression. Using a range of concentrations of angiotensin II (2×10^-8 to 2×10^-5 mol/l) a significant reduction in activity was seen but only at supra-physiological concentrations, [e.g. 2×10^-6 mol/l at 4 h pretreatment: 36.7±2.0 pmol cortisone·h^-1·mg^-1 (mean±S.E.M.) compared with 45.1±1.7 pmol·h^-1·mg^-1 in control; P < 0.05]. The angiotensin-converting enzyme inhibitors captopril, enalapril, lisinopril, perindopril, quinapril and trandolapril at 10^-7 mol/l, but not fosinopril, significantly increased 11β-HSD2 activity after pretreatment for 16 or 24 h (P < 0.05-P < 0.01 compared with control). No effects were seen at 4 h pretreatment. Hydrochlorothiazide (10^-7 mol/l) significantly decreased 11β-HSD2 activity (P < 0.05 compared with control) at 4 h pretreatment. Commonly used diuretics, atrial natriuretic peptide and physiological concentrations of angiotensin II and bradykinin do not alter 11β-HSD2 activity. In contrast, a series of angiotensin-converting enzyme inhibitors significantly increase 11β-HSD2 activity in vitro. This may explain how intrarenal infusions of angiotensin-converting enzyme inhibitors increase renal sodium excretion independent of circulating concentrations of angiotensin II. The interaction between angiotensin-converting enzyme inhibitors and 11β-HSD2 may be an additional mechanism by which the former can lower blood pressure.