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

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

Author information

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.

PMID:
26437603
PMCID:
PMC4670583
DOI:
10.1016/j.cmet.2015.09.002
[Indexed for MEDLINE]
Free PMC Article

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