Dexamethasone and insulin activate serum and glucocorticoid‐inducible kinase 1 (SGK1) via different molecular mechanisms in cortical collecting duct cells

• Published in: Physiological reports Vol. 4; no. 10; pp. e12792 - n/a
• Main Authors: Mansley, Morag K., Watt, Gordon B., Francis, Sarah L., Walker, David J., Land, Stephen C., Bailey, Matthew A., Wilson, Stuart M.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.05.2016; John Wiley and Sons Inc
• Subjects: 1-Phosphatidylinositol 3-kinase; Animals; Cells, Cultured; Cellular and Molecular Endocrinology; Collecting duct; Cortical collecting duct; Dexamethasone; Dexamethasone - pharmacology; Enzyme Activation - drug effects; Enzyme Activation - physiology; epithelial Na+ channel; Gene expression; Glucocorticoids; Hormones; Immediate-Early Proteins - metabolism; Insulin; Insulin - pharmacology; Kidney; Kidney Cortex - drug effects; Kidney Cortex - enzymology; Kidney Tubules, Collecting - drug effects; Kidney Tubules, Collecting - enzymology; Kinases; Latency; Mice; Molecular modelling; Na+ transport; Original Research; Physiology; Protein kinase; Protein-Serine-Threonine Kinases - metabolism; Renal Absorption, Reabsorption and Secretion; renal Na+ retention; Rodents; Signalling Pathways; Sodium; Sodium channels; Steroids; Ussing chamber; United Kingdom > UK; Cortical collecting duct; Ussing chamber; renal Na+ retention; epithelial Na+ channel; Na+ transport
• ISSN: 2051-817X; 2051-817X
• DOI: 10.14814/phy2.12792

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. Strict hormonal control of Na+ reabsorption within the distal tubules of the nephron contributes to total body Na+ and volume homeostasis, thus contributing to the long term control of arterial blood pressure. Here, we demonstrate that the steroid hormone dexamethasone and the peptide hormone insulin stimulate ENaC‐mediated Na+ transport via the serum‐ and glucocorticoid‐inducible kinase 1 by distinct molecular mechanisms.