Activation of Cardiac Fibroblast Growth Factor Receptor 4 Causes Left Ventricular Hypertrophy.
Activation of Cardiac Fibroblast Growth Factor Receptor 4 Causes Left Ventricular Hypertrophy.
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DOI：
10.1016/j.cmet.2015.09.002
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发表时间：
2015-12-01
期刊：
影响因子：
29
通讯作者：
Faul C
中科院分区：
文献类型：
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作者：
Grabner A;Amaral AP;Schramm K;Singh S;Sloan A;Yanucil C;Li J;Shehadeh LA;Hare JM;David V;Martin A;Fornoni A;Di Marco GS;Kentrup D;Reuter S;Mayer AB;Pavenstädt H;Stypmann J;Kuhn C;Hille S;Frey N;Leifheit-Nestler M;Richter B;Haffner D;Abraham R;Bange J;Sperl B;Ullrich A;Brand M;Wolf M;Faul C
慢性肾脏病（CKD）是一种全球性的公共卫生威胁，可增加因心血管并发症（包括左心室肥大（LVH））导致的死亡风险。需要新的治疗靶点来设计治疗方法以减轻CKD的心血管负担。以前，我们证明了成纤维细胞生长因子（FGF）23的循环浓度在CKD中逐渐升高，并通过未知的FGF受体（FGFR）依赖性机制诱导LVH。在此，我们报道了FGF 23专门激活心肌细胞上的FGFR 4以刺激磷脂酶Cγ/钙调神经磷酸酶/活化T细胞核因子信号传导。一种特异性FGFR 4阻断抗体抑制FGF 23诱导的分离心肌细胞肥大并减轻CKD大鼠的LVH。缺乏FGFR 4的小鼠对升高的FGF 23不产生LVH，而携带FGFR 4功能获得性突变的敲入小鼠自发地产生LVH。因此，FGF 23通过激活FGFR 4促进LVH，从而将FGFR 4确立为降低CKD心血管风险的药理学靶点。
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 cells 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 knock-in 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.