Inhibition of 11 beta-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 exp lained by increased aldosterone concentrations. We therefore hypothesize th at 11 beta-hydroxysteroid dehydrogenase 2 (11 beta-HSD2), which protects mi neralocorticoid receptors (MR) from glucocorticosteroids, is down-regulated in cirrhosis. Cirrhosis was induced by bile duct ligation in rats. The uri nary ratio of (tetrahydrocorticosterone + 5 alpha-tetrahydrocorticosterone) /11-dehydro-tetrahydrocorticosterone [(THB+5 alpha-THB)/THA] was measured b y gas chromatography. Cortical collecting tubules (CCT) were isolated by mi crodissection and used for measurements of the activity of 11 beta-HSD2 by assessing the conversion of corticosterone to dehydrocorticosterone. The mR NA content of 11 beta-HSD2 was determined by reverse-transcription polymera se chain reaction (RT-PCR) in CCTs. The urinary ratio of (THB+5 alpha-THB)/ THA increased concomitantly with the urinary excretion of bile acids follow ing bile duct ligation, Chenodeoxycholic acid (CDCA) dose-dependently inhib ited 11 beta-HSD2 in CCT with a Ki of 19.9 mu mol/L. Four weeks after bile duct ligation, 11 beta-HSD2 activity was decreased in CCT, an observation p receded by a reduced mRNA content at weeks 2 and 3. In cirrhosis, the MR-pr otecting effect by 11 beta-HSD2 is diminished, and therefore, endogenous gl ucocorticoids can induce MR-mediated sodium retention and potassium loss.