Modulation of renal calcium handling by 11 beta-hydroxysteroid dehydrogenase type 2.
Reduced concentration of serum ionized calcium and increased urinary calcium excretion have been reported in primary aldosteronism and glucocorticoid-treated patients. A reduced activity of the 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta HSD2) results in overstimulation of the mineralocorticoid receptor by cortisol. Whether inhibition of the 11 beta HSD2 by glycyrrhetinic acid (GA) may increase renal calcium excretion is unknown. Serum and urinary electrolyte and creatinine, serum ionized calcium, urinary calcium excretion, and the steroid metabolites (THF+5 alpha THF)/THE as a parameter of 11 beta HSD2 activity were repeatedly measured in 20 healthy subjects during baseline conditions and during 1 wk of 500 mg/d GA. One week of GA induced a maximal increment of 93% in (THF+5 alpha THF)/THE. Ambulatory BP was significantly higher at day 7 of GA than at baseline (126/77 +/- 10/7 versus 115/73 +/- 8/6 mmHg; P < 0.001 for systolic; P < 0.05 for diastolic). During GA administration, serum ionized calcium decreased from 1.26 +/- 0.05 to 1.18 +/- 0.04 mmol/L (P < 0.0001), and absolute urinary calcium excretion was enhanced from 29.2 +/- 3.6 to 31.9 +/- 3.1 micromol/L GFR (P < 0.01). Fractional calcium excretion increased from 2.4 +/- 0.3 to 2.7 +/- 0.3% (P < 0.01) and was negatively correlated to the fractional sodium excretion during GA (R = -0.35; P < 0.001). Moreover, serum potassium correlated positively with serum ionized calcium (R = 0.66; P < 0.0001). Inhibition of 11 beta HSD2 activity is sufficient to significantly increase the fractional excretion of calcium and decrease serum ionized calcium, suggesting decreased tubular reabsorption of this divalent cation under conditions of renal glucocorticoid/mineralocorticoid excess. The likely site of steroid-regulated renal calcium handling appears to be the distal tubule.
Ferrari
Paolo
P
Division of Nephrology and Hypertension, Department of Pediatrics, Inselspital, University of Berne, Switzerland. paolo.ferrari@insel.ch
Bianchetti
Mario G
MG
Sansonnens
Aurelie
A
Frey
Felix J
FJ
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D005260:Female; D006034:Glycyrrhetinic Acid / Q000494:pharmacology*; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011188:Potassium / Q000097:blood; D011446:Prospective Studies; D013760:Tetrahydrocortisol / Q000378:metabolism; D013761:Tetrahydrocortisone / Q000378:metabolism
D013761:Tetrahydrocortisone; D013760:Tetrahydrocortisol; D006913:Hydroxysteroid Dehydrogenases; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C468387:HSD11B2 protein, human; D006034:Glycyrrhetinic Acid; D011188:Potassium; D002118:Calcium