A Novel Role for Glucocorticoid-induced Leucine Zipper Protein in Epithelial Sodium Channel-mediated Sodium Transport

Abstract

The steroid hormone aldosterone stimulates sodium (Na ؉ ) transport in tight epithelia by altering the expression of target genes that regulate the activity and trafficking of the epithelial sodium channel (ENaC Hormone-regulated sodium (Na ϩ ) transport in tight epithelia is essential for the control of circulatory volume, blood pressure, and extracellular fluid composition in vertebrates. The epithelial Na ϩ channel, ENaC, 5 constitutes the rate-limiting step for Na ϩ transport, and its activity, trafficking, and expression are important targets of regulation, most notably by the mineralocorticoid hormone aldosterone, which acts primarily through the mineralocorticoid receptor to alter the transcription of a set of target genes (1). Several studies using candidate gene approaches (2, 3) or unbiased screens (4 -8) have been undertaken to discern the mechanistic basis of aldosterone action. As with other steroid-regulated processes (9), two major classes of target genes have been identified: early and late. Early response genes appear to be required for initiation of the response, whereas the late response genes participate in consolidation (10). The latter include components of the ion transport machinery itself (for example, ENaC subunits and subunits of the Na,KATPase) and genes that encode regulatory proteins that likely act to limit the extent of the aldosterone response (for example, activators of the mitogen-activated protein kinase cascade, such as epidermal growth factor (EGF) or its receptor, epidermal growth factor receptor (11). The former category encodes primarily signaling molecules, implicated in pathways that control ENaC activity and/or trafficking (1). The best characterized of these targets is the serine-threonine kinase serum-and glucocorticoid-induced kinase-1 (SGK1) (1), which acts to increase apical membrane ENaC, at least in part, by inhibiting the ubiquitin ligase Nedd4Ϫ2, itself a modulator of ENaC trafficking and degradation (12, 13). Recently, several lines of evidence have suggested that aldosteroneregulated mediators other than SGK1 provide stimulatory input into this system (1). Most notably, although SGK1 knock-out mice have aldosterone resistance, their phenotype is substantially less severe than that of either mineralocorticoid receptor or ␣ENaC knock-out mice (1, 14) or of adrenalectomized wild type animals (15), suggesting that renal ENaC function and renal mineralocorticoid action are partially but not completely dependent on SGK1. The observation that short term aldosterone treatment induces an accumulation of SGK1 in the entire aldosterone-sensitive distal nephron, whereas the apical insertion of ENaC takes place only in the connecting tubule and early collecting duct, indicates that other factors are probably required as well to drive ENaC cell surface expression and activity and, thus, Na ϩ reabsorption (15). It is also notable that inhibitors of phosphatidylinositol 3Ј-kinase (which is responsible for activation of SGK1) do not completely abolish aldosterone-induced Na ...

Anti-inflammatory functions of glucocorticoid-induced genes

“…RNA interference experiments also supported a role for GILZ in the inhibition of CXCL8 expression in endothelial cells (Eddleston et al, 2007). On the other hand, GILZ stimulated rather than suppressed the expression and activity of the epithelial sodium channel α (ENaCα) (Bhalla et al, 2006;Soundararajan et al, 2005), possibly via inhibition of the ERK pathway (Ayroldi et al, 2002;Soundararajan et al, 2005). ENaCα expression is thought to contribute to GC-induced hypertension (Fuller et al, 2000;Itani et al, 2002;Sayegh et al, 1999;Stokes and Sigmund, 1998).…”

“…GCs upregulate glucocorticoid inducible leucine zipper (GILZ) expression in T cells (Asselin-Labat et al, 2004;D'Adamio et al, 1997;Mittelstadt and Ashwell, 2001;Riccardi et al, 2001), mast cells , eosinophils (Arthaningtyas et al, 2005), epithelial (Bhalla et al, 2006;Chivers et al, 2006;Eddleston et al, 2007;Soundararajan et al, 2005;Wang et al, 2004), and myeloid cells (Berrebi et al, 2003;Cohen et al, 2006;Ehrchen et al, 2007). Relatively high basal GILZ expression has also been recorded in brain, lung and skeletal muscle .…”

Epithelial sodium channel regulated by differential composition of a signaling complex

“…Recent evidence supports the idea that the Raf-interacting protein glucocorticoid-induced leucine zipper protein 1 (GILZ1) increases plasma membrane ENaC in part by antagonizing the inhibitory effect of the Raf-MEK-ERK module (10,11).…”

“…The use of EGF to activate ERK1/2 in these cells through stimulation of endogenous EGF receptor is well described (19,20), and we have shown that activated ERK1/2 inhibits surface ENaC and GILZ1 reverses this process (10). Hence HEK 293T cells offered a useful system for examining regulatory factors that potentially govern ENaC surface expression.…”

Role of caspase-8 in thymus function

“…Because of the variety of protein interactions and its abundance in several cell types, GILZ has, in fact, a crucial role in controlling protein trafficking and signaling. Most recently, novel functions have been defined, including regulation of T helper cell differentiation 72,73 and DC function, 74,75 increase of epithelial Na þ channel-mediated Na þ transport in the kidney, 76,77 and control of malignant transformation through inhibition of Ras-driven tumorigenesis. 71,78,79 Young adult GILZ-overexpressing transgenic mice exhibit dramatically reduced numbers of CD4 þ CD8 þ thymocytes and increased ex vivo thymocyte apoptosis.…”