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

Cell Metab. 2015 Dec 1;22(6):1020-32. doi: 10.1016/j.cmet.2015.09.002. Epub 2015 Oct 1.

Authors

Alexander Grabner¹, Ansel P Amaral², Karla Schramm², Saurav Singh², Alexis Sloan², Christopher Yanucil², Jihe Li³, Lina A Shehadeh⁴, Joshua M Hare³, Valentin David⁵, Aline Martin⁵, Alessia Fornoni¹, Giovana Seno Di Marco⁶, Dominik Kentrup⁶, Stefan Reuter⁶, Anna B Mayer⁶, Hermann Pavenstädt⁶, Jörg Stypmann⁷, Christian Kuhn⁸, Susanne Hille⁸, Norbert Frey⁸, Maren Leifheit-Nestler⁹, Beatrice Richter⁹, Dieter Haffner⁹, Reimar Abraham¹⁰, Johannes Bange¹⁰, Bianca Sperl¹¹, Axel Ullrich¹¹, Marcus Brand⁶, Myles Wolf¹², Christian Faul¹³

Affiliations

¹ Katz Family Drug Discovery Center and Division of Nephrology and Hypertension, Department of Medicine, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA.
² Katz Family Drug Discovery Center and Division of Nephrology and Hypertension, Department of Medicine, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA; Department of Cell Biology and Anatomy, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA.
³ Interdisciplinary Stem Cell Institute, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA; Division of Cardiology, Department of Medicine, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA.
⁴ Interdisciplinary Stem Cell Institute, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA; Division of Cardiology, Department of Medicine, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA; Vascular Biology Institute, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA.
⁵ Katz Family Drug Discovery Center and Division of Nephrology and Hypertension, Department of Medicine, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA; Division of Nephrology and Hypertension, Department of Medicine and Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
⁶ Department of Internal Medicine D, University Hospital Münster, 48149 Münster, Germany.
⁷ Division of Cardiology, Department of Cardiovascular Medicine, University Hospital Münster, 48149 Münster, Germany.
⁸ Department of Cardiology and Angiology, University Medical Center of Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
⁹ Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, 30625 Hannover, Germany.
¹⁰ U3 Pharma GmbH, 82152 Martinsried, Germany.
¹¹ Department of Molecular Biology, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
¹² Division of Nephrology and Hypertension, Department of Medicine and Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
¹³ Katz Family Drug Discovery Center and Division of Nephrology and Hypertension, Department of Medicine, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA; Department of Cell Biology and Anatomy, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA. Electronic address: cfaul@med.miami.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Calcineurin / metabolism
Cells, Cultured
Disease Models, Animal
Female
Fibroblast Growth Factor-23
Fibroblast Growth Factors / genetics
Fibroblast Growth Factors / metabolism
Gene Knock-In Techniques
Glucuronidase / genetics
Glucuronidase / metabolism
HEK293 Cells
Humans
Hypertrophy, Left Ventricular / metabolism
Hypertrophy, Left Ventricular / pathology*
Klotho Proteins
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutagenesis, Site-Directed
Myocytes, Cardiac / cytology
Myocytes, Cardiac / metabolism
NFATC Transcription Factors / metabolism
Phospholipase C gamma / metabolism
Rats
Rats, Sprague-Dawley
Receptor, Fibroblast Growth Factor, Type 4 / deficiency
Receptor, Fibroblast Growth Factor, Type 4 / genetics
Receptor, Fibroblast Growth Factor, Type 4 / metabolism*
Renal Insufficiency, Chronic / metabolism
Renal Insufficiency, Chronic / pathology
Signal Transduction

Substances

FGF23 protein, human
Fgf23 protein, mouse
NFATC Transcription Factors
Fibroblast Growth Factors
Fibroblast Growth Factor-23
Receptor, Fibroblast Growth Factor, Type 4
Calcineurin
Phospholipase C gamma
Glucuronidase
Klotho Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding