FGF23 regulates renal sodium handling and blood pressure. Issue 6 (5th May 2014)

• Record Type: Journal Article
• Authors: Andrukhova, Olena; Slavic, Svetlana; Smorodchenko, Alina; Zeitz, Ute; Shalhoub, Victoria; Lanske, Beate; Pohl, Elena E; Erben, Reinhold G
• Is Part Of: EMBO molecular medicine. Volume 6:Issue 6(2014:Jun.)
• Page Start: 744
• Page End: 759
• Publication Date: 2014-05-05
• Subjects: Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.1002/emmm.201303716
• Languages: English
• ISSNs: 1757-4676

Abstract

<abstract abstract-type="main" id="emmm201303716-abs-0001"> <title>Abstract</title> <p>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 <italic>Fgf23</italic> and α<italic>Klotho</italic> deficiency. Conversely, gain of FGF23 function by injection of wild‐type mice with recombinant FGF23 or by elevated circulating levels of endogenous Fgf23 in <italic>Hyp</italic> 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.</p> </abstract>