FGF23 acts directly on renal proximal tubules to induce phosphaturia through activation of the ERK1/2-SGK1 signaling pathway.
Fibroblast growth factor-23 (FGF23) is a bone-derived endocrine regulator of phosphate homeostasis which inhibits renal tubular phosphate reabsorption. Binding of circulating FGF23 to FGF receptors in the cell membrane requires the concurrent presence of the co-receptor αKlotho. It is still controversial whether αKlotho is expressed in the kidney proximal tubule, the principal site of phosphate reabsorption. Hence, it has remained an enigma as to how FGF23 downregulates renal phosphate reabsorption. Here, we show that renal proximal tubular cells do express the co-receptor αKlotho together with cognate FGF receptors, and that FGF23 directly downregulates membrane expression of the sodium-phosphate cotransporter NaPi-2a by serine phosphorylation of the scaffolding protein Na(+)/H(+) exchange regulatory cofactor (NHERF)-1 through ERK1/2 and serum/glucocorticoid-regulated kinase-1 signaling.
University of Veterinary Medicine Vienna, Vienna, Austria.
Olena
O
Andrukhova
Ute
U
Zeitz
Regina
R
Goetz
Moosa
M
Mohammadi
Beate
B
Lanske
Reinhold G
RG
Erben
D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007015:Hypophosphatemia, Familial / Q000201:enzymology* / Q000473:pathology*; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D000090265:Klotho Proteins; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases
D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors; D005966:Glucuronidase; D017874:Immediate-Early Proteins; D000090265:Klotho Proteins; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D017923:Sodium-Hydrogen Exchangers; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D000099184:Serum-Glucocorticoid Regulated Kinases; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; C093376:sodium-hydrogen exchanger regulatory factor