title: FGF23 promotes renal calcium reabsorption through the TRPV5 channel.
abstract: αKlotho is thought to activate the epithelial calcium channel Transient Receptor Potential Vanilloid-5 (TRPV5) in distal renal tubules through its putative glucuronidase/sialidase activity, thereby preventing renal calcium loss. However, αKlotho also functions as the obligatory co-receptor for fibroblast growth factor-23 (FGF23), a bone-derived phosphaturic hormone. Here, we show that renal calcium reabsorption and renal membrane abundance of TRPV5 are reduced in Fgf23 knockout mice, similar to what is seen in αKlotho knockout mice. We further demonstrate that αKlotho neither co-localizes with TRPV5 nor is regulated by FGF23. Rather, apical membrane abundance of TRPV5 in renal distal tubules and thus renal calcium reabsorption are regulated by FGF23, which binds the FGF receptor-αKlotho complex and activates a signaling cascade involving ERK1/2, SGK1, and WNK4. Our data thereby identify FGF23, not αKlotho, as a calcium-conserving hormone in the kidney.
authors.affiliation: University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Olena
authors.initials: O
authors.lastname: Andrukhova
authors.forename: Alina
authors.initials: A
authors.lastname: Smorodchenko
authors.forename: Monika
authors.initials: M
authors.lastname: Egerbacher
authors.forename: Carmen
authors.initials: C
authors.lastname: Streicher
authors.forename: Ute
authors.initials: U
authors.lastname: Zeitz
authors.forename: Regina
authors.initials: R
authors.lastname: Goetz
authors.forename: Victoria
authors.initials: V
authors.lastname: Shalhoub
authors.forename: Moosa
authors.initials: M
authors.lastname: Mohammadi
authors.forename: Elena E
authors.initials: EE
authors.lastname: Pohl
authors.forename: Beate
authors.initials: B
authors.lastname: Lanske
authors.forename: Reinhold G
authors.initials: RG
authors.lastname: Erben
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005966:Glucuronidase; D017874:Immediate-Early Proteins / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D050916:TRPV Cation Channels / Q000378:metabolism*; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D002118:Calcium; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors; D005966:Glucuronidase; D017874:Immediate-Early Proteins; D000090265:Klotho Proteins; D017346:Protein Serine-Threonine Kinases; D011956:Receptors, Cell Surface; D050916:TRPV Cation Channels; D000099184:Serum-Glucocorticoid Regulated Kinases; C000717428:Fgf23 protein, mouse; C499024:Prkwnk4 protein, mouse