Effects of peroxisome proliferator-activated receptor [gamma] agonists on Na+ transport and activity of the kinase SGK1 in epithelial cells from lung and kidney
Background and purpose: Peroxisome proliferator-activated receptor [gamma] (PPAR[gamma]) 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 th...
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Published in | British journal of pharmacology Vol. 159; no. 3; p. 678 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Blackwell Publishing Ltd
01.02.2010
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Online Access | Get full text |
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Summary: | Background and purpose: Peroxisome proliferator-activated receptor [gamma] (PPAR[gamma]) 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 PPAR[gamma] agonists stimulate epithelial Na+ absorption or alter the control of cellular SGK1 activity. It is therefore likely that other mechanisms are involved in PPAR[gamma]-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. [PUBLICATION ABSTRACT] |
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ISSN: | 0007-1188 1476-5381 |
DOI: | 10.1111/j.1476-5381.2009.00564.x |