Sgk1 Mediates Osmotic Induction of NPR-A Gene in Rat Inner Medullary Collecting Duct Cells

Songcang Chen, James A. McCormick, Kavitha Prabaker, Jian Wang, David Pearce, David G. Gardner

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

We have shown previously that increased extracellular osmolality stimulates expression and promoter activity of the type A natriuretic peptide receptor (NPR-A) gene in rat inner medullary collecting duct (IMCD) cells through a mechanism that involves activation of p38 mitogen-activated protein kinase (MAPK). The serum and glucocorticoid inducible kinase (Sgk) is thought to participate in the regulation of sodium handling in distal tubular segments. We sought to determine whether this kinase might be involved in the osmotic stimulation of NPR-A gene promoter activity. Exposure of cultured IMCD cells to an additional 75 mmol/L NaCl in culture media (final osmolality 475 mosm/kg) resulted in an ≈4-fold increase in Sgk1 protein levels after 7 hours. The Sgk1 induction was almost completely inhibited by the p38 MAPK inhibitor SB203580, indicating that NaCl activates Sgk1 through the p38 MAPK pathway. Transient transfection of a mouse Sgk1 expression vector along with a -1590 NPR-A luciferase reporter resulted in an ≈3-fold increment in reporter activity, which was significantly reduced by cotransfection with a kinase-dead Sgk1 mutant. The NaCl-dependent induction was partially blocked (≈40% inhibition) by cotransfection of the kinase-dead Sgk1 mutant. Neither Sgk1 nor the kinase-dead mutant had any effect on endothelial nitric oxide synthase (eNOS) promoter activity, and the Sgkl mutant and 8-bromo-cyclic guanosine monophosphate were, to some degree, additive in reducing osmotically stimulated NPR-A promoter activity. Collectively, these data imply that Sgk1 operates over an eNOS-independent, p38 MAPK-dependent pathway in mediating osmotic induction of the NPR-A gene promoter.

Original languageEnglish (US)
Pages (from-to)866-871
Number of pages6
JournalHypertension
Volume43
Issue number4
DOIs
StatePublished - Apr 1 2004

Keywords

  • Atrial natriuretic factor
  • Gene regulation
  • Glucocorticoids
  • Kinase
  • Receptors
  • Signal transduction

ASJC Scopus subject areas

  • Internal Medicine

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