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

Soundararajan R, Zhang TT, Wang J, Vandewalle A and Pearce D
Source: J Biol Chem
Publication Date: (2005)
Issue: 280(48): 39970-39981
Research Area:
Cells used in publication:
Species: mouse
Tissue Origin: kidney
Nucleofector® I/II/2b
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). We performed microarray analysis to identify aldosterone-regulated transcripts in mammalian kidney epithelial cells (mpkCCDc14). One target, glucocorticoid-induced leucine zipper protein (GILZ) was previously identified by SAGE analysis, however, its function in epithelial ion transport was unknown. Here we show that GILZ expression is rapidly stimulated by aldosterone in kidney epithelial cells (mpkCCDc14), and that GILZ, in turn, strongly stimulates ENaC-mediated Na+ transport by inhibiting extracellular signal-regulated kinase (ERK yen) signaling. In Xenopus oocytes with activated ERK, heterologous GILZ expression consistently inhibited phospho-ERK expression, and markedly stimulated ENaC-mediated Na+ current, in a manner similar to that of U0126 (a pharmacologic inhibitor of ERK signaling). In mpkCCDc14 cells, GILZ transfection similarly consistently inhibited phospho-ERK expression, and stimulated transepithelial Na+ transport. Furthermore, aldosterone treatment of mpkCCDc14 cells suppressed phospho-ERK levels with a time course that paralleled their increase of Na+ transport. Finally, GILZ expression markedly increased cell surface ENaC expression in EGF-treated mammalian kidney epithelial cells, HEK 293. These observations suggest a novel link between GILZ and regulation of epithelial sodium transport through modulation of ERK signaling, and could represent an important pathway for mediating aldosterone actions in health and disease.