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Inhibition of 11β‐hydroxysteroid dehydrogenase by bile acids in rats with cirrhosis
Author(s) -
Ackermann Daniel,
Vogt Bruno,
Escher Geneviève,
Dick Bernhard,
Reichen Jürg,
Frey Brigitte M.,
Frey Felix J.
Publication year - 1999
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.510300303
Subject(s) - medicine , endocrinology , chenodeoxycholic acid , cirrhosis , chemistry , corticosterone , aldosterone , mineralocorticoid receptor , mineralocorticoid , ligation , bile acid , biology , hormone
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 11β‐hydroxysteroid dehydrogenase 2 (11β‐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 + 5α‐tetrahydrocorticosterone)/ 11‐dehydro‐tetrahydrocorticosterone [(THB+5α‐THB)/THA] was measured by gas chromatography. Cortical collecting tubules (CCT) were isolated by microdis* and used for measurements of the activity of 11β‐HSD2 by assessing the conversion of corticosterone to dehydrocorticosterone. The mRNA content of 11β‐HSD2 was determined by reverse‐transcription polymerase chain reaction (RT‐PCR) in CCTs. The urinary ratio of (THB+5α‐THB)/THA increased concomitantly with the urinary excretion of bile acids following bile duct ligation. Chenodeoxycholic acid (CDCA) dose‐dependently inhibited 11β‐HSD2 in CCT with a K i of 19.9 μmol/L. Four weeks after bile duct ligation, 11β‐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 11β‐HSD2 is diminished, and therefore, endogenous glucocorticoids can induce MR‐mediated sodium retention and potassium loss.