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


METHODS
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.


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
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.
Wilson
Stuart M
SM
Centre for Cardiovascular and Lung Biology, Division of Medical Sciences, College of Medicine, Dentistry and Nursing, University of Dundee, Dundee, UK. S.M.Wilson@Dundee.ac.uk
Mansley
Morag K
MK
Getty
Jennet
J
Husband
Elaine M
EM
Inglis
Sarah K
SK
Hansen
Michael K
MK
D001692:Biological Transport / Q000187:drug effects; D002452:Cell Count; D004847:Epithelial Cells / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism*; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism*; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism; D000077205:Pioglitazone; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000819:agonists / Q000378:metabolism / Q000494:pharmacology*
D005938:Glucocorticoids; D007328:Insulin; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D010770:Phosphotransferases; D000077205:Pioglitazone