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

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Abstract
Peroxisome proliferator‐activated receptor gamma (PPARγ) 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 PPARγ 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 PPARγ agonists, paralleled by an increase in SGK1 mRNA that is abolished by pretreatment with a specific PPARγ antagonist, and that this leads to increased levels of cell surface ENaCα. Electrophoretic mobility shift assays suggest that these effects are caused by binding of PPARγ to a specific response element in the SGK1 promoter. Our results identify SGK1 as a target for PPARγ and suggest a novel role for PPARγ 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 PPARγ in man.

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