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Gewählte Publikation:

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Publikationstyp: Zeitschriftenaufsatz
Dokumenttyp: Originalarbeit

Jahr: 2014

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

Titel: FGF23 regulates renal sodium handling and blood pressure.

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



Autor/innen der Vetmeduni Vienna:

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

Beteiligte Vetmed-Organisationseinheiten
Institut für Physiologie, Pathophysiologie und Biophysik, Abteilung für Physiologie, Pathophysiologie und experimentelle Endokrinologie
Institut für Physiologie, Pathophysiologie und Biophysik, Abteilung für Physiologie und Biophysik


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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