Inhibition of 11beta-hydroxysteroid dehydrogenase by bile acids in rats with cirrhosis.
Renal sodium retention and potassium loss occur early, in many instances in the preascitic state of cirrhosis, an observation that cannot be fully explained by increased aldosterone concentrations. We therefore hypothesize that 11beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2), which protects mineralocorticoid receptors (MR) from glucocorticosteroids, is down-regulated in cirrhosis. Cirrhosis was induced by bile duct ligation in rats. The urinary ratio of (tetrahydrocorticosterone + 5alpha-tetrahydrocorticosterone)/ 11-dehydro-tetrahydrocorticosterone [(THB+5alpha-THB)/THA] was measured by gas chromatography. Cortical collecting tubules (CCT) were isolated by microdissection and used for measurements of the activity of 11beta-HSD2 by assessing the conversion of corticosterone to dehydrocorticosterone. The mRNA content of 11beta-HSD2 was determined by reverse-transcription polymerase chain reaction (RT-PCR) in CCTs. The urinary ratio of (THB+5alpha-THB)/THA increased concomitantly with the urinary excretion of bile acids following bile duct ligation. Chenodeoxycholic acid (CDCA) dose-dependently inhibited 11beta-HSD2 in CCT with a Ki of 19.9 micromol/L. Four weeks after bile duct ligation, 11beta-HSD2 activity was decreased in CCT, an observation preceded by a reduced mRNA content at weeks 2 and 3. In cirrhosis, the MR-protecting effect by 11beta-HSD2 is diminished, and therefore, endogenous glucocorticoids can induce MR-mediated sodium retention and potassium loss.
Ackermann
D
D
Division of Nephrology, Departments of Medicine and Clinical Research, University of Berne, Berne, Switzerland.
Vogt
B
B
Escher
G
G
Dick
B
B
Reichen
J
J
Frey
B M
BM
Frey
F J
FJ
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000818:Animals; D002635:Chenodeoxycholic Acid / Q000494:pharmacology*; D003345:Corticosterone / Q000652:urine; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000235:genetics; D007685:Kidney Tubules, Collecting / Q000201:enzymology*; D008026:Ligation; D008106:Liver Cirrhosis, Experimental / Q000201:enzymology*; D008297:Male; D009569:Nitric Oxide / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
D012333:RNA, Messenger; D002635:Chenodeoxycholic Acid; D009569:Nitric Oxide; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D003345:Corticosterone