Effects of soluble Klotho and active vitamin D on FGF23-induced cardiac hypertrophy

成纤维细胞生长因子（FGF） 23在骨骼中产生，调节肾脏中磷酸盐的排泄以及血清中活性维生素D（也称为1,25D或骨化三醇）的水平。为此，FGF23与FGF受体(FGFR)-Klotho复合物结合。已经描述了四种不同的FGFR亚型，膜结合蛋白Klotho作为FGF23的共受体来支持FGFR结合。Klotho也以可溶性形式存在，可以在血液中检测到。当慢性肾病（CKD）进展过程中肾功能下降时，血清磷酸盐水平升高诱导FGF23生成增加。CKD的特征是FGF23水平升高高达1000倍，血清可溶性Klotho水平降低，1,25 d减少。在CKD患者中，这些改变与发生心血管疾病（包括心脏肥厚）的风险增加以及死亡率增加有关。在之前的机制研究中，我们发现FGF23可以在心肌细胞上结合FGFR4，从而激活由PLCγ/钙调神经磷酸酶/NFAT介导的细胞内促肥厚信号级联。本研究的假设是可溶性Klotho和/或1,25 d抑制fgf23诱导的心肌肥厚。我们将研究可溶性Klotho是否可以结合FGF23和/或FGFR4，从而阻断促肥厚级联或诱导心肌细胞中的不同信号通路。就1,25D而言，我们将研究其与维生素D受体的结合是否直接阻止fgfr4相关蛋白PLCγ的激活，从而阻断导致心脏肥厚的级联反应。如果成功，我们的结果可以作为一种新的、更有效的治疗CKD患者的治疗策略的基础，包括降低或阻断FGF23和增加血清可溶性Klotho和维生素D水平的组合。

The hormone fibroblast growth factor (FGF) 23 is produced in the bone and regulates the excretion of phosphate in the kidney as well as serum levels of active vitamin D (also termed 1,25D or calcitriol). To do so, FGF23 binds to the FGF receptor (FGFR)-Klotho complex. Four different FGFR isoforms have been described and the membrane-bound protein Klotho serves as a co-receptor for FGF23 to support FGFR binding. Klotho also exists as a soluble form that can be detected in the blood. When the kidney function declines during the progression of chronic kidney disease (CKD), rising serum phosphate levels induce an increase in FGF23 production. CKD is characterized by up to 1000-fold enhanced FGF23 levels, decreased serum levels of soluble Klotho and reduced 1,25D. In CKD patients, these alterations are associated with an increased risk of developing cardiovascular disease, including cardiac hypertrophy, as well as increased mortality. In pevious mechanistic studies we have found that FGF23 can bind FGFR4 on cardiomyocytes and thereby activate an intracellular pro-hypertrophic signaling cascade mediated by PLCγ/calcineurin/NFAT. The hypothesis of this study is that soluble Klotho and/or 1,25D inhibit FGF23-induced cardiac hypertrophie. We will investigate, if soluble Klotho can bind FGF23 and/or FGFR4 and either block the pro-hypertrophic cascade or induce a different signaling pathway in cardiomyocytes. In terms of 1,25D, we will study, if its binding to the vitamin D receptor directly prevents the activation of the FGFR4-linked protein PLCγ thereby blocking the cascade resulting in cardiac hypertrophy. If successful, our results could serve as the base for a novel, more efficient therapeutic strategy for the treatment of patients with CKD, including a combination of decreasing or blocking FGF23 and increasing serum levels of soluble Klotho and vitamin D.