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 Shehadeh, Joshua 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 H Faul

Research output: Contribution to journalArticle

222 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. Grabner et al. reveal that FGFR4 mediates the pro-hypertrophic cardiac effects of FGF23, a phosphate-regulating hormone elevated in patients with chronic kidney disease (CKD). Activation of FGFR4/calcineurin/NFAT signaling is sufficient to induce cardiac hypertrophy in mice, while FGFR4 blockade attenuates cardiac hypertrophy in a rat model of CKD.

Original languageEnglish (US)
JournalCell Metabolism
DOIs
StateAccepted/In press - Jan 23 2015

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

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    Grabner, A., Amaral, A. P., Schramm, K., Singh, S., Sloan, A., Yanucil, C., Li, J., Shehadeh, L., Hare, J., 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. H. (Accepted/In press). Activation of Cardiac Fibroblast Growth Factor Receptor 4 Causes Left Ventricular Hypertrophy. Cell Metabolism. https://doi.org/10.1016/j.cmet.2015.09.002