title: 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). We performed microarray analysis to identify aldosterone-regulated transcripts in mammalian kidney epithelial cells (mpkC-CD(c14)). One target, glucocorticoid-induced leucine zipper protein (GILZ), was previously identified by serial analysis of gene expression (SAGE); however, its function in epithelial ion transport was unknown. Here we show that GILZ expression is rapidly stimulated by aldosterone in mpkCCD(c14) and that GILZ, in turn, strongly stimulates ENaC-mediated Na+ transport by inhibiting extracellular signal-regulated kinase (ERK) 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 mpkCCD(c14) cells, GILZ transfection similarly consistently inhibited phospho-ERK expression and stimulated transepithelial Na+ transport. Furthermore, aldosterone treatment of mpkCCD(c14) 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 epidermal growth factor-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.
authors.affiliation: Division of Nephrology, Department of Medicine, University of California at San Francisco, San Francisco, California 94143-0532, USA.
authors.forename: Rama
authors.initials: R
authors.lastname: Soundararajan
authors.forename: Ting Ting
authors.initials: TT
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Alain
authors.initials: A
authors.lastname: Vandewalle
authors.forename: David
authors.initials: D
authors.lastname: Pearce
mesh_terms: D000450:Aldosterone / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D018076:DNA, Complementary / Q000378:metabolism; D015536:Down-Regulation; D004594:Electrophysiology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism; D053503:Epithelial Sodium Channels; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D007477:Ions; D007668:Kidney / Q000378:metabolism; D016350:Leucine Zippers; D051379:Mice; D008856:Microscopy, Fluorescence; D009570:Nitriles / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D009865:Oocytes / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011374:Progesterone / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D012964:Sodium / Q000737:chemistry / Q000378:metabolism*; D015222:Sodium Channels / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D014981:Xenopus; D014982:Xenopus laevis
chemical_list: D002070:Butadienes; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D053503:Epithelial Sodium Channels; D005938:Glucocorticoids; D007477:Ions; D009570:Nitriles; D015222:Sodium Channels; C113580:U 0126; D000450:Aldosterone; D011374:Progesterone; D012964:Sodium; D048049:Extracellular Signal-Regulated MAP Kinases