title: Dexamethasone and insulin activate serum and glucocorticoid-inducible kinase 1 (SGK1) via different molecular mechanisms in cortical collecting duct cells.
abstract: Serum and glucocorticoid-inducible kinase 1 (SGK1) is a protein kinase that contributes to the hormonal control of renal Na(+) retention by regulating the abundance of epithelial Na(+) channels (ENaC) at the apical surface of the principal cells of the cortical collecting duct (CCD). Although glucocorticoids and insulin stimulate Na(+) transport by activating SGK1, the responses follow different time courses suggesting that these hormones act by different mechanisms. We therefore explored the signaling pathways that allow dexamethasone and insulin to stimulate Na(+) transport in mouse CCD cells (mpkCCDcl4). Dexamethasone evoked a progressive augmentation of electrogenic Na(+) transport that became apparent after ~45 min latency and was associated with increases in SGK1 activity and abundance and with increased expression of SGK1 mRNA Although the catalytic activity of SGK1 is maintained by phosphatidylinositol-OH-3-kinase (PI3K), dexamethasone had no effect upon PI3K activity. Insulin also stimulated Na(+) transport but this response occurred with no discernible latency. Moreover, although insulin also activated SGK1, it had no effect upon SGK1 protein or mRNA abundance. Insulin did, however, evoke a clear increase in cellular PI3K activity. Our data are consistent with earlier work, which shows that glucocorticoids regulate Na(+) retention by inducing sgk1 gene expression, and also establish that this occurs independently of increased PI3K activity. Insulin, on the other hand, stimulates Na(+) transport via a mechanism independent of sgk1 gene expression that involves PI3K activation. Although both hormones act via SGK1, our data show that they activate this kinase by distinct physiological mechanisms.
authors.affiliation: Division of Pharmacy, School of Medicine, Pharmacy and Health, Durham University Queen's Campus, Stockton-on-Tees, UK morag.mansley@durham.ac.uk.
authors.forename: Morag K
authors.initials: MK
authors.lastname: Mansley
authors.affiliation: Medical Research Institute, College of Medicine, Dentistry and Nursing, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Watt
authors.affiliation: Division of Pharmacy, School of Medicine, Pharmacy and Health, Durham University Queen's Campus, Stockton-on-Tees, UK.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Francis
authors.affiliation: Medical Research Institute, College of Medicine, Dentistry and Nursing, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Walker
authors.affiliation: Medical Research Institute, College of Medicine, Dentistry and Nursing, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Land
authors.affiliation: The British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Bailey
authors.affiliation: Division of Pharmacy, School of Medicine, Pharmacy and Health, Durham University Queen's Campus, Stockton-on-Tees, UK.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Wilson
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D017874:Immediate-Early Proteins / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology*; D007672:Kidney Cortex / Q000187:drug effects / Q000201:enzymology*; D007685:Kidney Tubules, Collecting / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D003907:Dexamethasone; D017874:Immediate-Early Proteins; D007328:Insulin; D017346:Protein Serine-Threonine Kinases; D000099184:Serum-Glucocorticoid Regulated Kinases
keywords: Cortical collecting duct; Na+ transport; Ussing chamber; epithelial Na+ channel; renal Na+ retention