FGF23 regulates renal sodium handling and blood pressure

• Published in: EMBO molecular medicine 2014-06, Vol.6 (6), p.744-759
• Main Authors: Andrukhova, Olena, Slavic, Svetlana, Smorodchenko, Alina, Zeitz, Ute, Shalhoub, Victoria, Lanske, Beate, Pohl, Elena E, Erben, Reinhold G
• Format: Article
• Language: English
• Subjects: Abundance; aldosterone; Alfacalcidol; Animal models; Animals; Antihypertensive Agents - therapeutic use; Blood Pressure; Calcifediol; Cardiomegaly - metabolism; Cardiovascular diseases; Chlorothiazide - therapeutic use; Chronic kidney failure; Distal tubules; EMBO04; EMBO45; Extracellular signal-regulated kinase; Fibroblast Growth Factor-23; Fibroblast growth factors; Fibroblast Growth Factors - administration & dosage; Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - metabolism; Gene Deletion; Glucocorticoids; Glucuronidase - genetics; heart hypertrophy; Humans; Hypertension - drug therapy; Hypertension - genetics; Hypertension - metabolism; Hypertrophy; Kidney - metabolism; Kidney diseases; Kinases; Klotho Proteins; Lysine; Male; Menopause; Mice; Mice, Inbred C57BL; Mortality; Phosphates; Physiological aspects; Proximal tubules; Reabsorption; Recombinant Proteins - administration & dosage; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Renal function; Renal tubules; Research Article; Signal Transduction; Sodium; Sodium - metabolism; Sodium Chloride Symporter Inhibitors - therapeutic use; sodium homeostasis; Solute Carrier Family 12, Member 3 - genetics; Solute Carrier Family 12, Member 3 - metabolism; Up-Regulation; Vitamin D
• ISSN: 1757-4676; 1757-4684
• DOI: 10.1002/emmm.201303716

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 α Klotho 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. Synopsis 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. Graphical Abstract 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.