PPARγ activation enhances cell surface ENaCα via up‐regulation of SGK1 in human collecting duct cells

Abstract

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dependent transcription factor that belongs to the nuclear receptor family that plays a critical role in adipocyte differentiation and lipid metabolism. Here we report for the first time that PPARgamma is expressed in human renal cortical collecting ducts (CCD), segments of the nephor involved in regulation of sodium and water homeostasis via action of the epithelial sodium channel (ENaC). ENaC activity is regulated by the hormones aldosterone and insulin, primarily through co-ordinate actions on serum and glucocorticoid regulated kinase 1 (SGK1). We show that SGK1 activity is stimulated by treatment of a human CCD cell line with PPARgamma agonists, paralleled by an increase in SGK1 mRNA that is abolished by pretreatment with a specific PPARgamma antagonist, and that this leads to increased levels of cell surface ENaCalpha. Electrophoretic mobility shift assays suggest that these effects are caused by binding of PPARgamma to a specific response element in the SGK1 promoter. Our results identify SGK1 as a target for PPARgamma and suggest a novel role for PPARgamma in regulation of sodium re-absorption in the CCD via stimulation of ENaC activity. This pathway may play a role in sodium retention caused by activation of PPARgamma in man.

Lack of the serum and glucocorticoid-inducible kinase SGK1 attenuates the volume retention after treatment with the PPARγ agonist pioglitazone

“…The latter were in the lower micromolar range (10-15 μM), which is comparable to levels measured in volunteers after oral ingestion of 30 mg pioglitazone (3 μM; [44]). At those concentrations, pioglitazone does increase extracellular fluid volume, as previously shown for PPARγ agonists [18,22,49].…”

“…The use of the PPARγ agonists has, however, been impeded by their volume retaining properties [18,22,49]. In patients with congestive heart failure (CHF), treatment with PPARγ agonists was associated with decompensation and occurrence of pulmonary edema [35].…”

“…On the one hand, PPARγ agonists were found to upregulate mRNA levels of SCNN1G encoding for the gamma subunit of ENaC in a mouse inner medullary collecting duct cell line [19]. On the other hand PPARγ agonists have been shown to stimulate the transcription of the serum and glucocorticoid-inducible kinase SGK1 [22], which, in turn, was suggested to enhance the surface expression of ENaCα [22]. In three well-established cell culture models of the renal principal cell type, PPARγ agonists did not alter basal or insulin-stimulated ENaC activity and may thus be effective through additional mechanisms [36], which, at least in theory, could be similarly sensitive to SGK1.…”

Collecting duct-specific deletion of peroxisome proliferator-activated receptor γ blocks thiazolidinedione-induced fluid retention

“…This notion is supported by several lines of direct and indirect evidence from previous studies. First, in a cultured human cortical CD cell line, PPAR␥ agonists increase levels of cell surface ENaC␣, paralleled by stimulation of gene expression of serum and glucocorticoid regulated kinase 1 (SGK1), a key mediator of aldosterone activation of ENaC (29). Second, a PPAR␥ ligand, GI262570, increased expressions of ENaC␣, SGK1, and Na-K-ATPase␣ in the renal medulla (26).…”

Pioglitazone Use and Heart Failure in Patients With Type 2 Diabetes and Preexisting Cardiovascular Disease

“…The mechanisms of action behind the fluid retention with TZDs (e.g., cardiac cause or drug interaction with receptors on sodium channels) remain unclear, although it has been suggested that peroxisome proliferator-activated receptor-␥ may regulate sodium reabsorption in the cortical collecting ducts (segments of the nephron involved in regulation of sodium and water homeostasis) via stimulation of epithelial sodium channel activity (22). The long-term study of pioglitazone use and heart failure, funded by the American Diabetes Association (18), argues against the possibility that TZDs cause heart failure.…”