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

Abstract

Background and purpose: Peroxisome proliferator-activated receptor g (PPARg) 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 mM) and pioglitazone (10 mM) 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 PPARg agonists stimulate epithelial Na + absorption or alter the control of cellular SGK1 activity. It is therefore likely that other mechanisms are involved in PPARg-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.

Dexamethasone and insulin activate serum and glucocorticoid-inducible kinase 1 (SGK1) via different molecular mechanisms in cortical collecting duct cells

“…; Loffing and Korbmacher ; Wilson et al. ). It is therefore important to understand the mechanisms that allow glucocorticoids and insulin to regulate Na + retention within the distal nephron, and earlier work indicates that both hormones act via the serum and glucocorticoid‐inducible kinase 1 (SGK1), a protein kinase that contributes to the control of Na + retention by regulating the abundance of ENaC at the cell surface (De La Rosa et al.…”

Rapid elevation of sodium transport through insulin is mediated by AKT in alveolar cells

“…For example, a study of the respiratory cell line H441, supplemented with dexamethasone, showed no increased phosphorylation of NDRG1 after incubation with insulin (Wilson et al. ). In renal mpkCCD cells, however, the same study showed that the effect of insulin was critically dependent on activation of SGK1 (Wilson et al.…”

“…In renal mpkCCD cells, however, the same study showed that the effect of insulin was critically dependent on activation of SGK1 (Wilson et al. ). This suggests different regulatory mechanisms for channel activity between different cell types.…”

Peroxisome proliferator-activated receptor-γ agonists repress epithelial sodium channel expression in the kidney

“…Interestingly, in M1 cells we saw augmentation of Sgk-1 mRNA expression associated with PPAR␥ agonists. However, in mpkCCD cells, PPAR␥ ligands did not increase Sgk-1 mRNA or activity (32,54). Moreover, treatment with RGZ or pioglitazone for 10 days did not significantly alter the opening probability or Fig.…”

“…Several studies have suggested that PPAR␥-dependent fluid retention is related to upregulation of ENaC expression and function (11,16); however, to date, no direct transcriptional studies have been performed (47) and investigators have not shown that PPAR␥ ligand treatment is associated with increases in kidney ENaC␥ mRNA or protein expression (11). Furthermore, growing evidence suggests that PPAR␥ agonists do not directly enhance ENaC activity or expression (32,36,45,52,54), and mice with knockdown of ENaC␣ in the collecting duct still develop edema in response to TZD treatment (52). In our studies, we were consistently able to show fluid retention associated with TZDs; however, this was not associated with renal upregulation of ENaC isoform mRNA and protein subunits as previously posited.…”