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HSD2 activity
1 Physiology and Pharmacology, University of Southern Denmark, Odense, Denmark; Laboratory of Nephropatholog, Odense University Hospital, Odense, Denmark
2 Physiology and Pharmacology, University of Southern Denmark, Odense, Denmark
3 Institute of Pathology, Odense University Hospital, Odense, Ecuador
4 Endocrinology Unit, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom
* To whom correspondence should be addressed. E-mail: oskott{at}health.sdu.dk.
Down-regulation of the renal glucocorticoid-metabolizing enzyme 11
-hydroxysteroid dehydrogenase type 2 (11-HSD-2) during liver cirrhosis may allow activation of the mineralocorticoid receptor (MR) by glucocorticoids and contribute to sodium retention. We tested this hypothesis in male Wistar rats with decompensated liver cirrhosis and ascites 7 weeks after bile duct ligation (BDL). Renal 11-HSD-2 mRNA, protein and activity were significantly decreased in decompensated rats. The urinary Na+ /K+ ratio was reduced by 40 %. Renal ENaC mRNA and immunostaining were only slightly affected. Complete metabolic studies, including faecal excretion, showed that the BDL rats had avid renal sodium retention. Treatment of the BDL rats with dexamethasone suppressed endogenous glucocorticoid production, normalized total sodium balance and renal sodium excretion, and reduced ascites formation to the same degree as direct inhibition of MR with K+-canrenoate. Total potassium balance was negative in the BDL rats, while renal potassium excretion was unchanged. In the distal colon, expression of ENaC were increased in BDL rats. Faecal potassium excretion was increased in cirrhotic rats, and this was corrected by treatment with K+-canrenoate but not by dexamethasone. We conclude that development of sodium retention and decompensation in cirrhotic rats is associated with down-regulation of renal 11-HSD-2 activity and inappropriate activation of renal sodium reabsorption by endogenous glucocorticoids. In addition, the overall potassium loss in the BDL model is due to increased faecal potassium excretion, which is associated with up-regulation of ENaC in distal colon.
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