FGF23 regulates renal sodium handling and blood pressure
Article first published online: 5 MAY 2014
© 2014 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EMBO Molecular Medicine
Volume 6, Issue 6, pages 744–759, June 2014
How to Cite
EMBO Mol Med (2014) 6: 744–759
- Issue published online: 3 JUN 2014
- Article first published online: 5 MAY 2014
- Manuscript Accepted: 6 MAR 2014
- Manuscript Revised: 27 FEB 2014
- Manuscript Received: 25 NOV 2013
- Austrian Science Fund. Grant Number: FWF P24186-B21
- University of Veterinary Medicine Vienna
- blood pressure;
- fibroblast growth factor-23;
- heart hypertrophy;
- sodium homeostasis
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.
FGF23 serum levels are elevated in chronic kidney disease patients. FGF23 is here shown to be a regulator of the sodium-chloride channel NCC in distal renal tubules, thus affecting renal sodium retention, plasma expansion, hypertension, and heart hypertrophy.
- FGF23 regulates membrane abundance and activity of the renal sodium-chloride channel NCC through the ERK1/2-SGK1-WNK4 signaling pathway.
- FGF23 is a sodium-conserving hormone.
- Elevated circulating FGF23 leads to volume expansion, hypertension, and cardiac hypertrophy in a Klotho-dependent fashion.
- The NCC inhibitor chlorothiazide blunts FGF23-induced hypertension.
- A low sodium diet aggravates the hypertensive action of FGF23 through crosstalk with aldosterone signaling at the level of SGK1.