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.
authors.affiliation: 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.
authors.forename: Alexander
authors.initials: A
authors.lastname: Grabner
authors.affiliation: 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.
authors.forename: Ansel P
authors.initials: AP
authors.lastname: Amaral
authors.affiliation: 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.
authors.forename: Karla
authors.initials: K
authors.lastname: Schramm
authors.affiliation: 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.
authors.forename: Saurav
authors.initials: S
authors.lastname: Singh
authors.affiliation: 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.
authors.forename: Alexis
authors.initials: A
authors.lastname: Sloan
authors.affiliation: 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.
authors.forename: Christopher
authors.initials: C
authors.lastname: Yanucil
authors.affiliation: 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.
authors.forename: Jihe
authors.initials: J
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Lina A
authors.initials: LA
authors.lastname: Shehadeh
authors.affiliation: 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.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Hare
authors.affiliation: 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.
authors.forename: Valentin
authors.initials: V
authors.lastname: David
authors.affiliation: 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.
authors.forename: Aline
authors.initials: A
authors.lastname: Martin
authors.affiliation: 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.
authors.forename: Alessia
authors.initials: A
authors.lastname: Fornoni
authors.affiliation: Department of Internal Medicine D, University Hospital Münster, 48149 Münster, Germany.
authors.forename: Giovana Seno
authors.initials: GS
authors.lastname: Di Marco
authors.affiliation: Department of Internal Medicine D, University Hospital Münster, 48149 Münster, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Kentrup
authors.affiliation: Department of Internal Medicine D, University Hospital Münster, 48149 Münster, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Reuter
authors.affiliation: Department of Internal Medicine D, University Hospital Münster, 48149 Münster, Germany.
authors.forename: Anna B
authors.initials: AB
authors.lastname: Mayer
authors.affiliation: Department of Internal Medicine D, University Hospital Münster, 48149 Münster, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Pavenstädt
authors.affiliation: Division of Cardiology, Department of Cardiovascular Medicine, University Hospital Münster, 48149 Münster, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Stypmann
authors.affiliation: Department of Cardiology and Angiology, University Medical Center of Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kuhn
authors.affiliation: Department of Cardiology and Angiology, University Medical Center of Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Hille
authors.affiliation: Department of Cardiology and Angiology, University Medical Center of Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Frey
authors.affiliation: Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Leifheit-Nestler
authors.affiliation: Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Richter
authors.affiliation: Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Haffner
authors.affiliation: U3 Pharma GmbH, 82152 Martinsried, Germany.
authors.forename: Reimar
authors.initials: R
authors.lastname: Abraham
authors.affiliation: U3 Pharma GmbH, 82152 Martinsried, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Bange
authors.affiliation: Department of Molecular Biology, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Sperl
authors.affiliation: Department of Molecular Biology, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Ullrich
authors.affiliation: Department of Internal Medicine D, University Hospital Münster, 48149 Münster, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Brand
authors.affiliation: 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.
authors.forename: Myles
authors.initials: M
authors.lastname: Wolf
authors.affiliation: 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.
authors.forename: Christian
authors.initials: C
authors.lastname: Faul
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D055879:Gene Knock-In Techniques; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism / Q000473:pathology*; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051436:Renal Insufficiency, Chronic / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction
chemical_list: C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D050778:NFATC Transcription Factors; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D051499:Receptor, Fibroblast Growth Factor, Type 4; D019703:Calcineurin; D051966:Phospholipase C gamma; D005966:Glucuronidase; D000090265:Klotho Proteins