Regulation of sodium-potassium adenosine triphosphate subunit gene expression by corticosteroids and 11 beta-hydroxysteroid dehydrogenase activity.
The induction of Na,K-ATPase plays a vital role in mediating epithelial sodium transport. Although its activity is regulated by corticosteroids, it is uncertain whether this is predominantly by mineralo- or glucocorticoid mechanisms. 11 beta-Hydroxysteroid dehydrogenase (11 beta HSD) catalyzes the interconversion of active corticosterone (B) to inactive 11-dehydrocorticosterone and protects the nonselective mineralocorticoid receptor (MR) from glucocorticoid excess. We have studied the regulation of the alpha 1- and beta 1-subunits of Na,K-ATPase by mineralo- and glucocorticoids in vitro and in vivo, and how this is modulated by 11 beta HSD activity. Cultured rat kidney epithelial cells (NRK 52-E) expressed 11 beta HSD activity, which was inhibited by the licorice derivative glycyrrhetinic acid (GE). Dexamethasone, aldosterone, and high concentrations of B (1-10 microM) increased Na,K-ATPase alpha 1 and beta 1 messenger RNA (mRNA) levels, an effect that was inhibited by coincubation with the MR antagonist RU 26752, but not by the glucocorticoid receptor antagonist RU 38486. GE, which itself reduced Na,K-ATPase alpha 1/beta 1 mRNA levels, potentiated the action of B, so that low concentrations of B (10 nM) increased Na,K-ATPase alpha 1/beta 1 mRNA levels. In contrast, in vivo, RU 26752 and RU 38486 given ip for 4 days (n = 6/group) reduced renal Na,K-ATPase alpha 1 and beta 1 levels. Glycyrrhizic acid also inhibited both renal 11 beta HSD mRNA and activity and levels of Na,K-ATPase alpha 1/beta 1 mRNA. In vivo renal Na,K-ATPase subunit mRNA levels are regulated by both mineralo- and glucocorticoid mechanisms. In vitro, however, although NRK 52-E cells expressed the glucocorticoid receptor, corticosteroid regulation of Na,K-ATPase, even by dexamethasone, occurred exclusively via the MR, suggesting that accessory transcription factors required for glucocorticoid hormone action are absent in this cell line. Finally, although the licorice derivatives GE and glycyrrhizic acid reduced Na,K-ATPase alpha 1/beta 1 mRNA levels, they also potentiated the stimulatory effect of B by inhibiting its metabolism via 11 beta HSD, establishing 11 beta HSD as an important prereceptor modulator of mineralocorticoid hormone action.
Whorwood
C B
CB
Department of Medicine, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, United Kingdom.
Ricketts
M L
ML
Stewart
P M
PM
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000305:Adrenal Cortex Hormones / Q000502:physiology*; D000818:Animals; D005786:Gene Expression Regulation; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D019695:Glycyrrhizic Acid; D006913:Hydroxysteroid Dehydrogenases / Q000187:drug effects / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics*; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology
D000305:Adrenal Cortex Hormones; D012333:RNA, Messenger; D013148:Spironolactone; D015735:Mifepristone; D019695:Glycyrrhizic Acid; C047175:7-propyl spirolactone; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D000254:Sodium-Potassium-Exchanging ATPase; D006034:Glycyrrhetinic Acid