FGF23 acts directly on renal proximal tubules to induce phosphaturia through activation of the ERK1/2–SGK1 signaling pathway

• Published in: Bone (New York, N.Y.) Vol. 51; no. 3; pp. 621 - 628
• Main Authors: Andrukhova, Olena, Zeitz, Ute, Goetz, Regina, Mohammadi, Moosa, Lanske, Beate, Erben, Reinhold G
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.09.2012; Elsevier; Elsevier Science
• Subjects: Animals; Biological and medical sciences; Enzyme Activation - drug effects; Epithelial Cells - drug effects; Epithelial Cells - enzymology; Epithelial Cells - pathology; Fibroblast Growth Factor-23; Fibroblast Growth Factors - pharmacology; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; Glucuronidase - genetics; Glucuronidase - metabolism; Humans; Hypophosphatemia, Familial - enzymology; Hypophosphatemia, Familial - pathology; Immediate-Early Proteins - genetics; Immediate-Early Proteins - metabolism; Kidney; Kidney Tubules, Proximal - drug effects; Kidney Tubules, Proximal - enzymology; Kidney Tubules, Proximal - pathology; Klotho; Klotho Proteins; Male; MAP Kinase Signaling System - drug effects; Mice; Mice, Inbred C57BL; Models, Biological; Orthopedics; Phosphate homeostasis; Phosphoproteins - metabolism; Phosphorylation - drug effects; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Rapid Communication; Sodium-Hydrogen Exchangers - metabolism; Sodium-Phosphate Cotransporter Proteins, Type IIa - metabolism; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Mice; Fibroblast growth factor-23; Klotho; Phosphate homeostasis; Kidney; Phosphates; Proximal; Fibroblast growth factor; Rodentia; Homeostasis; Activation; Vertebrata; Renal tubule; Mammalia; Mouse; Animal; Morphology
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2012.05.015

Abstract 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.