Journal
CELL METABOLISM
Volume 22, Issue 6, Pages 1020-1032Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2015.09.002
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Funding
- Stifterverband fur die Deutsche Wissenschaft
- Simon-Claussen-Stiftung [H1405409999915626]
- Deutsche Forschungs Gemeinschaft [GR 4228/1-1, SFB656 C7]
- Roche
- Max Planck Society
- Daiichi-Sankyo
- State of Florida [3KN05]
- Florida Heart Research Institute
- Starr Foundation
- American Heart Association
- American Society of Nephrology
- U3 Pharma GmbH, Germany
- NIH [F30DK091057, F31DK10236101, F31DK09566101, R01DK090316, R01DK104753, K01AG040468, R01HL110737, R01HL094849, R01HL107110, R01HL084275, R01DK076116, K24DK093723, R01HL128714]
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Chronic kidney disease (CKD) is a worldwide public health threat that increases risk of death due to cardiovascular complications, including left ventricular hypertrophy (LVH). Novel therapeutic targets are needed to design treatments to alleviate the cardiovascular burden of CKD. Previously, we demonstrated that circulating concentrations of fibroblast growth factor (FGF) 23 rise progressively in CKD and induce LVH through an unknown FGF receptor (FGFR)-dependent mechanism. Here, we report that FGF23 exclusively activates FGFR4 on cardiac myocytes to stimulate phospholipase C gamma/calcineurin/nuclear factor of activated T cell signaling. A specific FGFR4-blocking antibody inhibits FGF23-induced hypertrophy of isolated cardiac myocytes and attenuates LVH in rats with CKD. Mice lacking FGFR4 do not develop LVH in response to elevated FGF23, whereas knockin mice carrying an FGFR4 gain-of-function mutation spontaneously develop LVH. Thus, FGF23 promotes LVH by activating FGFR4, thereby establishing FGFR4 as a pharmacological target for reducing cardiovascular risk in CKD.
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