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

In the kidney and colon 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) inactivates cortisol to cortisone, thereby protecting the non-selective mineralocorticoid receptor from cortisol. Deficiency of 11 beta-HSD2 results in cortisol-mediated sodium retention and hypertension, suggesting that the physiological regulation of 11 beta-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 11 beta-HSD2 (K-m for cortisol 66 nmol/l). Bradykinin (10(-8) to 10(-1)2 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 11 beta-HSD2 expression. Using a range of concentrations of angiotensin II (2 x 10(-8) to 2 x 10(-5) mol/l) a significant reduction in activity was seen but only at supra-physiological concentrations, [e.g. 2 x 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 11 beta-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 11 beta-HSD2 activity (P < 0.05 compared with control) at 4h pretreatment. Commonly used diuretics, atrial natriuretic peptide and physiological concentrations of angiotensin II and bradykinin do not alter 11 beta-HSD2 activity. In contrast, a series of angiotensin-converting enzyme inhibitors significantly increase 11 beta-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 11 beta-HSD2 may be an additional mechanism by which the former can lower blood pressure.