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Effects of peroxisome proliferator‐activated receptor γ agonists on Na + transport and activity of the kinase SGK1 in epithelial cells from lung and kidney
Author(s) -
Wilson Stuart M,
Mansley Morag K,
Getty Jennet,
Husband Elaine M,
Inglis Sarah K,
Hansen Michael K
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00564.x
Subject(s) - sgk1 , peroxisome proliferator activated receptor , receptor , lung , kidney , chemistry , peroxisome , endocrinology , medicine , kinase , microbiology and biotechnology , biology , biochemistry
Background and purpose: Peroxisome proliferator‐activated receptor γ (PPARγ) 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 µM) and pioglitazone (10 µM) 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 PPARγ agonists stimulate epithelial Na + absorption or alter the control of cellular SGK1 activity. It is therefore likely that other mechanisms are involved in PPARγ‐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.