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.
Animals Antihypertensive Agents/therapeutic use Blood Pressure* Cardiomegaly/metabolism Chlorothiazide/therapeutic use Fibroblast Growth Factors/administration & dosage Fibroblast Growth Factors/genetics Fibroblast Growth Factors/metabolism* Gene Deletion Glucuronidase/genetics Humans Hypertension/drug therapy Hypertension/genetics Hypertension/metabolism* Kidney/metabolism* Male Mice Mice, Inbred C57BL Recombinant Proteins/administration & dosage Recombinant Proteins/genetics Recombinant Proteins/metabolism Signal Transduction Sodium/metabolism* Sodium Chloride Symporter Inhibitors/therapeutic use Solute Carrier Family 12, Member 3/genetics Solute Carrier Family 12, Member 3/metabolism Up-Regulation