A novel role for glucocorticoid-induced leucine zipper protein in epithelial sodium channel-mediated sodium transport.
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.
Soundararajan
Rama
R
Division of Nephrology, Department of Medicine, University of California at San Francisco, San Francisco, California 94143-0532, USA.
Zhang
Ting Ting
TT
Wang
Jian
J
Vandewalle
Alain
A
Pearce
David
D
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
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