Effects of peroxisome proliferator-activated receptor gamma agonists on Na+ transport and activity of the kinase SGK1 in epithelial cells from lung and kidney

Stuart M Wilson, Morag K Mansley, Jennet Getty, Elaine M Husband, Sarah K Inglis, Michael K Hansen

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND AND PURPOSE: Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, such as rosiglitazone and pioglitazone, sensitize cells to insulin, and are therefore used to treat type 2 diabetes. However, in some patients, these drugs induce oedema, and the present study tests the hypothesis that this side effect reflects serum and glucocorticoid-inducible kinase 1 (SGK1)-dependent enhancement of epithelia Na(+) absorption.

EXPERIMENTAL APPROACH: Na(+) absorbing epithelial cells (H441 cells, mpkCCD cells) on permeable membranes were mounted in Ussing chambers, and the effects of rosiglitazone (2 microM) and pioglitazone (10 microM) on transepithelial Na(+) absorption were quantified electrometrically. Changes in SGK1 activity were assessed by monitoring phosphorylation of residues within an endogenous protein.

KEY RESULTS: Both cell types absorbed Na(+) via an electrogenic process that was enhanced by insulin. In mpkCCD cells, this stimulation of Na(+) transport was associated with increased activity of SGK1, whereas insulin regulated Na(+) transport in H441 cells through a mechanism that did not involve activation of this kinase. Rosiglitazone and pioglitazone had no discernible effect on transepithelial Na(+) absorption in unstimulated or insulin-stimulated cells and failed to alter cellular SGK1 activity.

CONCLUSIONS AND IMPLICATIONS: Our results do not support the view that PPARgamma agonists stimulate epithelial Na(+) absorption or alter the control of cellular SGK1 activity. It is therefore likely that other mechanisms are involved in PPARgamma-mediated fluid retention, and a better understanding of these mechanisms may help with the identification of patients likely to develop oedema or heart failure when treated with these drugs.

Original languageEnglish
Pages (from-to)678-88
Number of pages11
JournalBritish Journal of Pharmacology
Volume159
Issue number3
DOIs
Publication statusPublished - 1 Feb 2010

Keywords

  • Biological Transport
  • Cell Count
  • Epithelial Cells
  • Epithelium
  • Glucocorticoids
  • Humans
  • Insulin
  • Kidney
  • Lung
  • PPAR gamma
  • Phosphorylation
  • Phosphotransferases
  • Thiazolidinediones

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