Down-regulation of hepatic and renal 11 beta-hydroxysteroid dehydrogenase in rats with liver cirrhosis.
OBJECTIVE
11 beta-Hydroxysteroid dehydrogenase (11 beta-OHSD) enzymes are responsible for the interconversion of active 11 beta-hydroxycorticosteroids into inactive 11-ketoglucocorticosteroids and by that mechanism regulate the intracellular access of the steroids to the cognate receptor. A down-regulation of the shuttle of active to inactive glucocorticoids enhances access of glucocorticosteroids to both the glucocorticoid and the mineralocorticoid receptors. In liver cirrhosis, enhanced mineralocorticoid and glucocorticoid effects are observed. We therefore investigated the impact of liver cirrhosis after bile duct ligation on the transcription and activity of 11 beta-OHSD1 and 11 beta-OHSD2 in the corresponding tissues.


METHODS
Messenger RNA from 11 beta-OHSD1 and 11 beta-OHSD2 was assessed by reverse-transcription polymerase chain reaction; activity was assessed by measuring the interconversion of corticosterone to dehydrocorticosterone. The effect of bile and bile salts was determined using COS-1 cells transfected with 11 beta-OHSD1 or 11 beta-OHSD2.


RESULTS
In liver tissue, the messenger RNA ratios of 11 beta-OHSD1 to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) levels and, in kidney tissue, the ratios of 11 beta-OHSD2 to GAPDH levels decreased after induction of liver cirrhosis. The 11 beta-OHSD activities were correspondingly reduced. Bile and individual bile salts inhibited 11 beta-OHSD1 and 11 beta-OHSD2 oxidative activity in transfected COS-1 cells.


CONCLUSIONS
These findings indicate that in liver cirrhosis the mineralocorticoid and glucocorticoid receptor-protecting effects by the 11 beta-OHSD isoenzymes are down-regulated and that by the same mechanism the glucocorticoid and mineralocorticoid effects are enhanced.
Escher
G
G
Department of Medicine, University of Berne, Switzerland.
Nawrocki
A
A
Staub
T
T
Vishwanath
B S
BS
Frey
B M
BM
Reichen
J
J
Frey
F J
FJ
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000818:Animals; D019556:COS Cells; D015536:Down-Regulation; D006913:Hydroxysteroid Dehydrogenases / Q000096:biosynthesis*; D007668:Kidney / Q000201:enzymology* / Q000473:pathology; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000201:enzymology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases