Whorwood C B, Ricketts M L, Stewart P M
Department of Medicine, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, United Kingdom.
Endocrinology. 1994 Sep;135(3):901-10. doi: 10.1210/endo.135.3.8070385.
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.
钠钾 - ATP酶的诱导在介导上皮钠转运中起着至关重要的作用。尽管其活性受皮质类固醇调节，但尚不确定这主要是通过盐皮质激素还是糖皮质激素机制。11β - 羟基类固醇脱氢酶（11βHSD）催化活性皮质酮（B）向无活性的11 - 脱氢皮质酮的相互转化，并保护非选择性盐皮质激素受体（MR）免受糖皮质激素过量的影响。我们已经在体外和体内研究了盐皮质激素和糖皮质激素对钠钾 - ATP酶α1和β1亚基的调节，以及这是如何通过11βHSD活性进行调节的。培养的大鼠肾上皮细胞（NRK 52 - E）表达11βHSD活性，甘草衍生的甘草次酸（GE）可抑制该活性。地塞米松、醛固酮和高浓度的B（1 - 10μM）可增加钠钾 - ATP酶α1和β1信使核糖核酸（mRNA）水平，与MR拮抗剂RU 26752共同孵育可抑制该作用，但糖皮质激素受体拮抗剂RU 38486则无此作用。GE本身可降低钠钾 - ATP酶α1/β1 mRNA水平，但能增强B的作用，使得低浓度的B（10 nM）也可增加钠钾 - ATP酶α1/β1 mRNA水平。相反，在体内，腹腔注射RU 26752和RU 38486 4天（每组n = 6）可降低肾钠钾 - ATP酶α1和β1水平。甘草酸也可抑制肾11βHSD mRNA以及活性和钠钾 - ATP酶α1/β1 mRNA水平。体内肾钠钾 - ATP酶亚基mRNA水平受盐皮质激素和糖皮质激素机制的共同调节。然而在体外，尽管NRK 52 - E细胞表达糖皮质激素受体，但即使是地塞米松，其对钠钾 - ATP酶的皮质类固醇调节也仅通过MR发生，这表明该细胞系中缺乏糖皮质激素作用所需的辅助转录因子。最后，尽管甘草衍生的GE和甘草酸降低了钠钾 - ATP酶α1/β1 mRNA水平，但它们也通过抑制B经11βHSD的代谢而增强了B的刺激作用，确立了11βHSD作为盐皮质激素作用的重要受体前调节因子的地位。
