Studies of renal epithelial cells have shown that glucocorticoid-inducible leucine zipper proteins (GILZ1-3) contribute to the hormonal control of epithelial Na⁺ channel (ENaC) activity by suppressing signalling via the extracellular signal regulated kinases (ERK1/2) and by potentiating the effects of serum and glucocorticoid-inducible kinase 1 (SGK1) upon the abundance of ENaC in the membrane (Soundararajan et al., 2005, 2009). Moreover, recent work from this laboratory (Watt et al. 2009) has shown that transient expression of GILZ1 mimics the effects of glucocorticoid stimulation by activating an endogenous, Na⁺-permeable conductance in hormone-deprived H441 human airway epithelial cells. Since glucocorticoids are also known to control the α-ENaC gene transcription via a mechanism that is supressed by ERK1/2 (Wang et al., 2000), the present study has explored the effects of GILZ1-3 upon the dexamethasone-induced activation of a reporter gene construct incorporating 2.2 kb upstream sequence of the α-ENaC gene promoter. Initial studies showed that U1026 (10 µM), an inhibitor of ERK1/2, enhanced that response to maximally effective concentrations of dexamethasone (Fig 1A), a result which accords well with earlier work (Wang et al. 2000). Although the EC₅₀ values for dexamethasone measured in cells expressing GILZ1-3 (GILZ1: 4.5 ± 0.6 µM; GILZ2: 4.8 ± 0.7 µM; GILZ3: 1.9 ± 1.6 µM) did not differ significantly from the corresponding control values (4.8 ± 0.4 µM; 4.2 ± 0.6 µM and 2.1 ± 0.2 µM respectively), each of these proteins caused clear inhibition of the responses to maximally-effective concentrations of dexamethasone (Fig 1B-C). Transient expression of GILZ1-3 therefore supress α-ENaC gene transcription via a mechanism that cannot be attributed to inhibition of ERK1/2. It is therefore possible that these proteins may permit negative feedback control over the expression of this gene in glucocorticoid-stimulated cells.