Sodium homeostasis in terrestrial and freshwater vertebrates is controlled by the corticosteroid hormones, principally aldosterone, which stimulate electrogenic Na ؉ absorption in tight epithelia. Although aldosterone is known to increase apical membrane Na ؉ permeability in target cells through changes in gene transcription, the mechanistic basis of this effect remains poorly understood. The predominant early effect of aldosterone is to increase the activity of the epithelial sodium channel (ENaC), although ENaC mRNA and protein levels do not change initially.Rather, the open probability and͞or number of channels in the apical membrane are greatly increased by unknown modulators. To identify hormone-stimulated gene products that modulate ENaC activity, a subtracted cDNA library was generated from A6 cells, a stable cell line of renal distal nephron origin, and the effect of candidates on ENaC activity was tested in a coexpression assay. We report here the identification of sgk (serum and glucocorticoid-regulated kinase), a member of the serine-threonine kinase family, as an aldosterone-induced regulator of ENaC activity. sgk mRNA and protein were strongly and rapidly hormone stimulated both in A6 cells and in rat kidney. Furthermore, sgk stimulated ENaC activity approximately 7-fold when they were coexpressed in Xenopus laevis oocytes. These data suggest that sgk plays a central role in aldosterone regulation of Na ؉ absorption and thus in the control of extracellular f luid volume, blood pressure, and sodium homeostasis.
The androgen and glucocorticoid hormones elicit divergent and often opposing effects in cells, tissues, and animals. A wide range of physiological and molecular biological evidence suggests that the receptors that mediate these effects, the androgen and glucocorticoid receptors (AR and GR, respectively), influence each other's transcriptional activity. We now show that coexpressed AR and GR indeed do interact at the transcriptional level and that this interaction is correlated with their ability to form heterodimers at a common DNA site, in vitro and in vivo. Furthermore, mutants that cannot heterodimerize do not inhibit each other's activity. These observations provide the first evidence that the opposing physiological effects of the androgen and glucocorticoid hormones are due to the direct physical interaction between their receptors at the transcriptional level.The androgen and glucocorticoid hormones have profound effects on metabolism, animal behavior, and cellular proliferation. They act through intracellular receptors, members of the nuclear receptor superfamily, that exert their effects by binding to specific DNA sites and modulating the transcriptional activity of linked genes (for review see Ref. 1). Several mammalian tissues coexpress the receptors for these two hormones, and in a number of these tissues they have opposing effects (2-9). For example, the androgens act through the androgen receptor (AR) 1 to stimulate protein synthesis in skeletal muscle and to increase smooth muscle and prostate proliferation. Additionally, androgen receptors may be involved directly or indirectly in triggering aggressive dominant male behavior (2, 5, 7). In contrast, glucocorticoids act through the glucocorticoid receptor (GR) to cause skeletal muscle protein degradation and to inhibit smooth muscle and prostate proliferation and are correlated with submissive behavior in male rats (2,5,6,8,9). These opposing effects of androgens and glucocorticoids appear to reflect interaction at some level in their signaling pathways since glucocorticoids inhibit both the proliferative and anabolic effects of androgens (7, 9).AR and GR display a high degree of sequence homology, particularly in their DNA-binding domains (DBDs), and bind to a common DNA site termed a hormone response element (HRE) (10). Receptor specificity does not appear to be determined primarily by protein-DNA interaction, since their transcriptional activities differ markedly in some contexts (Fig. 1 and Refs. 11-13). It appears that factors other than DNA affinity control GR and AR activity at different types of HREs, as has been described previously for GR and its close relative, the mineralocorticoid receptor (MR) (14 -17).HREs contain imperfect palindromes composed of two halfsites that AR, GR, and MR bind as head-to-head homodimers, and recent evidence has suggested that, in addition to homodimer formation, MR and GR heterodimerize (16,18). In view of these observations, it seemed plausible that AR and GR might also interact directly through heterodime...
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