title: FGF23 regulates renal sodium handling and blood pressure.
abstract: Fibroblast growth factor-23 (FGF23) is a bone-derived hormone regulating renal phosphate reabsorption and vitamin D synthesis in renal proximal tubules. Here, we show that FGF23 directly regulates the membrane abundance of the Na(+):Cl(-) co-transporter NCC in distal renal tubules by a signaling mechanism involving the FGF receptor/αKlotho complex, extracellular signal-regulated kinase 1/2 (ERK1/2), serum/glucocorticoid-regulated kinase 1 (SGK1), and with-no lysine kinase-4 (WNK4). Renal sodium (Na(+)) reabsorption and distal tubular membrane expression of NCC are reduced in mouse models of Fgf23 and αKlotho deficiency. Conversely, gain of FGF23 function by injection of wild-type mice with recombinant FGF23 or by elevated circulating levels of endogenous Fgf23 in Hyp mice increases distal tubular Na(+) uptake and membrane abundance of NCC, leading to volume expansion, hypertension, and heart hypertrophy in a αKlotho and dietary Na(+)-dependent fashion. The NCC inhibitor chlorothiazide abrogates FGF23-induced volume expansion and heart hypertrophy. Our findings suggest that FGF23 is a key regulator of renal Na(+) reabsorption and plasma volume, and may explain the association of FGF23 with cardiovascular risk in chronic kidney disease patients.
authors.affiliation: University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Olena
authors.initials: O
authors.lastname: Andrukhova
authors.affiliation: University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Slavic
authors.affiliation: University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Alina
authors.initials: A
authors.lastname: Smorodchenko
authors.affiliation: University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Ute
authors.initials: U
authors.lastname: Zeitz
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Shalhoub
authors.affiliation: Harvard School of Dental Medicine, Boston, MA, USA.
authors.forename: Beate
authors.initials: B
authors.lastname: Lanske
authors.affiliation: University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Elena E
authors.initials: EE
authors.lastname: Pohl
authors.affiliation: University of Veterinary Medicine Vienna, Vienna, Austria Reinhold.Erben@vetmeduni.ac.at.
authors.forename: Reinhold G
authors.initials: RG
authors.lastname: Erben
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001794:Blood Pressure; D006332:Cardiomegaly / Q000378:metabolism; D002740:Chlorothiazide / Q000627:therapeutic use; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D005966:Glucuronidase / Q000235:genetics; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism*; D049993:Sodium Chloride Symporter Inhibitors / Q000627:therapeutic use; D064486:Solute Carrier Family 12, Member 3 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000959:Antihypertensive Agents; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D011994:Recombinant Proteins; D049993:Sodium Chloride Symporter Inhibitors; D064486:Solute Carrier Family 12, Member 3; D005346:Fibroblast Growth Factors; D002740:Chlorothiazide; D000089703:Fibroblast Growth Factor-23; D012964:Sodium; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: aldosterone; blood pressure; fibroblast growth factor‐23; heart hypertrophy; sodium homeostasis