Activation of Cardiac Fibroblast Growth Factor Receptor 4 Causes Left Ventricular Hypertrophy

Alexander Grabner; Ansel P. Amaral; Karla Schramm; Saurav Singh; Alexis Sloan; Christopher Yanucil; Jihe Li; Lina A. Shehadeh; Joshua M. Hare; Valentin David; Aline Martin; Alessia Fornoni; Giovana Seno Di Marco; Dominik Kentrup; Stefan Reuter; Anna B. Mayer; Hermann Pavenstädt; Jörg Stypmann; Christian Kuhn; Susanne Hille; Norbert Frey; Maren Leifheit-Nestler; Beatrice Richter; Dieter Haffner; Reimar Abraham; Johannes Bange; Bianca Sperl; Axel Ullrich; Marcus Brand; Myles Wolf; Christian Faul

doi:10.1016/j.cmet.2015.09.002

Activation of Cardiac Fibroblast Growth Factor Receptor 4 Causes Left Ventricular Hypertrophy

Alexander Grabner, Ansel P. Amaral, Karla Schramm, Saurav Singh, Alexis Sloan, Christopher Yanucil, Jihe Li, Lina A. Shehadeh, Joshua M. Hare, Valentin David, Aline Martin, Alessia Fornoni, Giovana Seno Di Marco, Dominik Kentrup, Stefan Reuter, Anna B. Mayer, Hermann Pavenstädt, Jörg Stypmann, Christian Kuhn, Susanne HilleNorbert Frey, Maren Leifheit-Nestler, Beatrice Richter, Dieter Haffner, Reimar Abraham, Johannes Bange, Bianca Sperl, Axel Ullrich, Marcus Brand, Myles Wolf, Christian Faul^*

^*Corresponding author for this work

Medicine, Nephrology Division

Research output: Contribution to journal › Article › peer-review

444 Scopus citations

Abstract

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 Cγ/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.

Original language	English (US)
Pages (from-to)	1020-1032
Number of pages	13
Journal	Cell Metabolism
Volume	22
Issue number	6
DOIs	https://doi.org/10.1016/j.cmet.2015.09.002
State	Published - 2015

Funding

The authors declare competing financial interests: M.W. has served as a consultant or received honoraria from Amgen, Keryx, Lutipold, Opko, Pfizer, and Sanofi. R.A. and J.B. are employees of U3 Pharma GmbH, Germany. A.G. was supported by Roche, A.U. by Daiichi-Sankyo, and C.F. by U3 Pharma GmbH, Germany. A.F. is an inventor on pending patents aimed to diagnose or treat proteinuric renal diseases and stands to gain royalties from their future commercialization. A.F. is a consultant for Hoffman-La Roche, Genentech, Janssen, Mesoblast, Abbvie, Boehringer Ingelheim, Alexion, Bristol Meyer Squibb, and Pfizer. This study was supported by the Stifterverband für die Deutsche Wissenschaft and Simon-Claussen-Stiftung (H1405409999915626 to M.B.), the Deutsche Forschungs Gemeinschaft (GR 4228/1-1 to A.G. and SFB656 C7 to S.R.), Roche (A.G.), the Max Planck Society (A.U.), Daiichi-Sankyo (A.U.), State of Florida (3KN05) and Florida Heart Research Institute (L.A.S.), the Starr Foundation (J.M.H.), the American Heart Association (A.G., M.W., and C.F.), the American Society of Nephrology (C.F.), U3 Pharma GmbH, Germany (C.F.), and grants F30DK091057 (A.P.A.), F31DK10236101 (K.S.), F31DK09566101 (A.S.), R01DK090316 (A.F.), R01DK104753 (A.F.), K01AG040468 (L.A.S.), R01HL110737 (J.M.H.), R01HL094849 (J.M.H.), R01HL107110 (J.M.H.), R01HL084275 (J.M.H.), R01DK076116 (M.W.), K24DK093723 (M.W.), and R01HL128714 (C.F.) from NIH. Gabriel Gaidosh (University of Miami Miller School of Medicine) assisted with confocal microscopy, and Johannes Backs (University of Heidelberg) with establishing the neonatal mouse ventricular myocyte cultures. Makoto Kuro-o (University of Texas Southwestern) provided FGFR and klotho cDNA constructs, Timothy McKinsey (University of Colorado) the anti-RCAN1 antibody, and Thomas Mariani (University of Rochester Medical Center) the global FGFR4 knockout mouse line.

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

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Grabner, A., Amaral, A. P., Schramm, K., Singh, S., Sloan, A., Yanucil, C., Li, J., Shehadeh, L. A., Hare, J. M., David, V., Martin, A., Fornoni, A., Di Marco, G. S., Kentrup, D., Reuter, S., Mayer, A. B., Pavenstädt, H., Stypmann, J., Kuhn, C., ... Faul, C. (2015). Activation of Cardiac Fibroblast Growth Factor Receptor 4 Causes Left Ventricular Hypertrophy. Cell Metabolism, 22(6), 1020-1032. https://doi.org/10.1016/j.cmet.2015.09.002

@article{e129940366444dd49e740c431590a76a,

title = "Activation of Cardiac Fibroblast Growth Factor Receptor 4 Causes Left Ventricular Hypertrophy",

abstract = "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 Cγ/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.",

author = "Alexander Grabner and Amaral, {Ansel P.} and Karla Schramm and Saurav Singh and Alexis Sloan and Christopher Yanucil and Jihe Li and Shehadeh, {Lina A.} and Hare, {Joshua M.} and Valentin David and Aline Martin and Alessia Fornoni and {Di Marco}, {Giovana Seno} and Dominik Kentrup and Stefan Reuter and Mayer, {Anna B.} and Hermann Pavenst{\"a}dt and J{\"o}rg Stypmann and Christian Kuhn and Susanne Hille and Norbert Frey and Maren Leifheit-Nestler and Beatrice Richter and Dieter Haffner and Reimar Abraham and Johannes Bange and Bianca Sperl and Axel Ullrich and Marcus Brand and Myles Wolf and Christian Faul",

note = "Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

doi = "10.1016/j.cmet.2015.09.002",

language = "English (US)",

volume = "22",

pages = "1020--1032",

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Grabner, A, Amaral, AP, Schramm, K, Singh, S, Sloan, A, Yanucil, C, Li, J, Shehadeh, LA, Hare, JM, David, V , Martin, A, Fornoni, A, Di Marco, GS, Kentrup, D, Reuter, S, Mayer, AB, Pavenstädt, H, Stypmann, J, Kuhn, C, Hille, S, Frey, N, Leifheit-Nestler, M, Richter, B, Haffner, D, Abraham, R, Bange, J, Sperl, B, Ullrich, A, Brand, M, Wolf, M & Faul, C 2015, 'Activation of Cardiac Fibroblast Growth Factor Receptor 4 Causes Left Ventricular Hypertrophy', Cell Metabolism, vol. 22, no. 6, pp. 1020-1032. https://doi.org/10.1016/j.cmet.2015.09.002

TY - JOUR

T1 - Activation of Cardiac Fibroblast Growth Factor Receptor 4 Causes Left Ventricular Hypertrophy

AU - Grabner, Alexander

AU - Amaral, Ansel P.

AU - Schramm, Karla

AU - Singh, Saurav

AU - Sloan, Alexis

AU - Yanucil, Christopher

AU - Li, Jihe

AU - Shehadeh, Lina A.

AU - Hare, Joshua M.

AU - David, Valentin

AU - Martin, Aline

AU - Fornoni, Alessia

AU - Di Marco, Giovana Seno

AU - Kentrup, Dominik

AU - Reuter, Stefan

AU - Mayer, Anna B.

AU - Pavenstädt, Hermann

AU - Stypmann, Jörg

AU - Kuhn, Christian

AU - Hille, Susanne

AU - Frey, Norbert

AU - Leifheit-Nestler, Maren

AU - Richter, Beatrice

AU - Haffner, Dieter

AU - Abraham, Reimar

AU - Bange, Johannes

AU - Sperl, Bianca

AU - Ullrich, Axel

AU - Brand, Marcus

AU - Wolf, Myles

AU - Faul, Christian

PY - 2015

Y1 - 2015

N2 - 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 Cγ/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.

AB - 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 Cγ/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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SP - 1020

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JF - Cell Metabolism

IS - 6

ER -

Activation of Cardiac Fibroblast Growth Factor Receptor 4 Causes Left Ventricular Hypertrophy

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