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

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.