PPARgamma activation enhances cell surface ENaCalpha via up-regulation of SGK1 in human collecting duct cells.
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.
Hong
Guizhu
G
Translational Medicine and Technology, GlaxoSmithKline, ACCI, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2GG, UK. Guizhu_2_Hong@gsk.com
Lockhart
Andrew
A
Davis
Bill
B
Rahmoune
Hassan
H
Baker
Sharon
S
Ye
Liang
L
Thompson
Paul
P
Shou
Yaping
Y
O'Shaughnessy
Kevin
K
Ronco
Pierre
P
Brown
John
J
D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D053503:Epithelial Sodium Channels; D006801:Humans; D017874:Immediate-Early Proteins; D007685:Kidney Tubules, Collecting / Q000201:enzymology / Q000378:metabolism*; D008954:Models, Biological; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D020218:Response Elements; D015222:Sodium Channels / Q000378:metabolism*; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism*; D015533:Transcriptional Activation; D015854:Up-Regulation; D000099184:Serum-Glucocorticoid Regulated Kinases
D053503:Epithelial Sodium Channels; D017874:Immediate-Early Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D015222:Sodium Channels; D014157:Transcription Factors; D000099184:Serum-Glucocorticoid Regulated Kinases