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
N1 - Funding Information:
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.
Funding Information:
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.
Publisher Copyright:
© 2015 Elsevier Inc.
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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U2 - 10.1016/j.cmet.2015.09.002
DO - 10.1016/j.cmet.2015.09.002
M3 - Article
C2 - 26437603
AN - SCOPUS:84945942478
VL - 22
SP - 1020
EP - 1032
JO - Cell Metabolism
JF - Cell Metabolism
SN - 1550-4131
IS - 6
ER -
