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Type of publication: Journal Article
Type of document: Full Paper

Year: 2014

Authors: Andrukhova, O; Slavic, S; Smorodchenko, A; Zeitz, U; Shalhoub, V; Lanske, B; Pohl, EE; Erben, RG

Title: FGF23 regulates renal sodium handling and blood pressure.

Source: EMBO Mol Med. 2014; 6(6):744-759



Authors Vetmeduni Vienna:

Andrukhova Olena
Erben Reinhold
Pohl Elena
Slavic Svetlana
Smorodchenko Alina
Zeitz Ute

Vetmed Research Units
Institute of Physiology, Pathohysiology and Biophysics, Unit of Physiology and Biophysics
Institute of Physiology, Pathohysiology and Biophysics, Unit of Physiology, Pathophysiology, and Experimental Endocrinology


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.

Keywords Pubmed: 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


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