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

被引：453

作者：

Grabner, Alexander ^{[1
,2
]}

Amaral, Ansel P. ^{[1
,2
,3
]}

Schramm, Karla ^{[1
,2
,3
]}

Singh, Saurav ^{[1
,2
,3
]}

Sloan, Alexis ^{[1
,2
,3
]}

Yanucil, Christopher ^{[1
,2
,3
]}

Li, Jihe ^{[4
,5
]}

Shehadeh, Lina A. ^{[4
,5
,6
]}

Hare, Joshua M. ^{[4
,5
]}

David, Valentin ^{[1
,2
,7
,8
]}

Martin, Aline ^{[1
,2
,7
,8
]}

Fomoni, Alessia ^{[1
,2
]}

Di Marco, Giovana Seno ^{[9
]}

Kentrup, Dominik ^{[9
]}

Reuter, Stefan ^{[9
]}

Mayer, Anna B. ^{[9
]}

Pavenstadt, Hermann ^{[9
]}

Stypmann, Joerg ^{[10
]}

Kuhn, Christian ^{[11
]}

Hille, Susanne ^{[11
]}

Frey, Norbert ^{[11
]}

Leifheit-Nestler, Maren ^{[12
]}

Richter, Beatrice ^{[12
]}

Haffner, Dieter ^{[12
]}

Abraham, Reimar ^{[13
]}

Bange, Johannes ^{[13
]}

Sperl, Bianca ^{[14
]}

Ullrich, Axel ^{[14
]}

Brand, Marcus ^{[9
]}

Wolf, Myles ^{[7
,8
]}

Faul, Christian ^{[1
,2
,3
]}

机构：

[1] Univ Miami, Leonard M Miller Sch Med, Dept Med, Katz Family Drug Discovery Ctr, Miami, FL 33136 USA

[2] Univ Miami, Leonard M Miller Sch Med, Dept Med, Div Nephrol & Hypertens, Miami, FL 33136 USA

[3] Univ Miami, Leonard M Miller Sch Med, Dept Cell Biol & Anat, Miami, FL 33136 USA

[4] Univ Miami, Leonard M Miller Sch Med, Interdisciplinary Stem Cell Inst, Miami, FL 33136 USA

[5] Univ Miami, Leonard M Miller Sch Med, Dept Med, Div Cardiol, Miami, FL 33136 USA

[6] Univ Miami, Leonard M Miller Sch Med, Vasc Biol Inst, Miami, FL 33136 USA

[7] Northwestern Univ, Feinberg Sch Med, Dept Med, Inst Publ Hlth & Med,Div Nephrol & Hypertens, Chicago, IL 60611 USA

[8] Northwestern Univ, Feinberg Sch Med, Ctr Translat Metab & Hlth, Inst Publ Hlth & Med, Chicago, IL 60611 USA

[9] Univ Hosp Munster, Dept Internal Med, D-48149 Munster, Germany

[10] Univ Hosp Munster, Div Cardiol, Dept Cardiovasc Med, D-48149 Munster, Germany

[11] Univ Med Ctr Schleswig Holstein, Dept Cardiol & Angiol, D-24105 Kiel, Germany

[12] Hannover Med Sch, Dept Pediat Kidney Liver & Metab Dis, D-30625 Hannover, Germany

[13] U3 Pharma GmbH, D-82152 Martinsried, Germany

[14] Max Planck Inst Biochem, Dept Mol Biol, D-82152 Martinsried, Germany

来源：

CELL METABOLISM | 2015年 / 22卷 / 06期

关键词：

FGF RECEPTOR; POINT MUTATION; KIDNEY-DISEASE; BINDING; KLOTHO; SPECIFICITY; EXPRESSION; INHIBITOR; MORTALITY; BLOCKADE;

D O I：

10.1016/j.cmet.2015.09.002

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 C gamma/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.

引用

页码：1020 / 1032

页数：13

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