Consequences of Elevated Fibroblast Growth Factor 23 in the Presence and Absence of Kidney Disease

项目总结 慢性肾病已成为一种世界性流行病，约有2600万人受到影响 仅在美国。慢性肾脏疾病(CKD)患者的主要死因/完 阶段性肾病(ESRD)是由尿毒症心肌病和中层血管钙化导致的 心血管死亡(CVD)。CKD/ESRD的CVD的病因是多因素的，尽管已经取得了进展 在治疗相关的合并症方面，CKD/ESRD患者的存活率并不显著 改进了。成纤维细胞生长因子23(FGF23)是一种由骨骼分泌的磷酸激素，它的水平升高 在CKD早期维持正常的磷酸盐血症，并随着CKD进展到ESRD而继续增加到 超生理学水平。流行病学研究表明，FGF23与心血管疾病的增加有关 CKD/ESRD的死亡率/发病率。然而，关于FGF23在以下方面的直接影响，有相互矛盾的数据 使用动物模型和人类观察研究心脏和血管系统。因此，人类的生物学 目前对FGF23知之甚少，有必要确定FGF23对心血管系统的影响。 肾脏疾病中的系统。申请人的实验室已经开发出一种创新的鼠标模型，具有 肾脏成纤维细胞生长因子受体(FGFRs)的复合缺失：肾脏条件性FGFR1和 FGFR4(KCFgfr1-/-/FGFR4-/-小鼠)导致FGF23水平慢性升高而不伴有低磷血症 由于肾脏抵抗FGF23的磷酸尿酸作用。申请者的长期目标是确定 FGF23在健康和肾脏疾病中的作用，特别是在慢性肾脏病、肾脏疾病的发生发展中的作用 纤维化、炎症、骨矿化和神经认知功能。使用上述鼠标 模型中，这项提议的总体目标是确定FGF23对心血管的直接影响 肾脏疾病中的系统。我们的初步数据表明，慢性心脏病患者心脏重量增加。 在6个月龄时暴露于FGF23并伴有高磷血症，并有主动脉增厚 12-18月龄小鼠的钙化。我们将确定FGF23需要引起的其他因素 心脏重量增加，因为KCFgfr1-/-/FGFR4-/-小鼠有轻度高磷血症，如肾脏 疾病。我们将使用不同的饮食方案来梳理出FGF23需要哪些额外的因素来 对心脏有不良影响：高磷血症、尿毒症毒素或两者兼而有之。有了这个 研究建议，我们还将研究负责血管平滑转换的信号通路 肌肉细胞转化为软骨细胞样细胞，促进血管钙化。我们的目标是确定FGFR 除信号通路外，还负责促进血管钙化。由此产生的结果是 该提案将为新的治疗靶点提供途径，以减轻FGF23对心血管的影响 这将对慢性肾脏病/终末期肾病患者的心血管死亡率/发病率产生积极影响。

PROJECT SUMMARY Chronic kidney disease has become a worldwide epidemic with approximately 26 million people being affected in the United States alone. The primary cause of death in patients with chronic kidney disease (CKD)/ end stage renal disease (ESRD) is from uremic cardiomyopathy and medial vascular calcification resulting in cardiovascular death (CVD). The etiology of CVD in CKD/ESRD is multifactorial, and despite advances made in treating the associated co-morbidities, the survival of patients with CKD/ESRD has not significantly improved. Fibroblast growth factor 23 (FGF23), a phosphaturic hormone secreted by the bone, is elevated early in CKD to maintain normophosphatemia, and, continues to increase with progression of CKD to ESRD to supraphysiological levels. Epidemiological studies have associated FGF23 with increased cardiovascular mortality/morbidity in CKD/ESRD. However, there is conflicting data regarding the direct effects of FGF23 on the heart and the vasculature using animal models and human observational studies. Thus, the biology of FGF23 is poorly understood and there is a need to determine the effects of FGF23 on the cardiovascular system in kidney disease. The applicant's laboratory has developed an innovative mouse model with a compound deletion of fibroblast growth factor receptors (Fgfrs) in the kidney: Kidney Conditional Fgfr1 and Fgfr4 (KCFgfr1-/-/Fgfr4-/- mice) which results in chronic elevation of FGF23 levels without hypophosphatemia due to renal resistance to the phosphaturic actions of FGF23. The applicant's long term goal is to identify the role of FGF23 in health and kidney disease especially in regards to development/progression of CKD, renal fibrosis, inflammation, bone mineralization, and neurocognitive functions. Using the above described mouse model, the overall objective for this proposal is to identify the direct effects of FGF23 on the cardiovascular system in kidney disease. Our preliminary data indicates that there is increased cardiac mass with chronic exposure to FGF23 together with hyperphosphatemia at 6 months of age and there is increased aortic calcification in 12-18 month old mice. We will determine the additional factors that FGF23 requires to cause increased cardiac mass as KCFgfr1-/-/Fgfr4-/- mice have modest hyperphosphatemia, as seen in kidney disease. We will use different dietary regimens to tease out which additional factors are required for FGF23 to have the adverse effects on the heart: hyperphosphatemia, uremic toxins or a combination of both. With this research proposal, we will also study the signaling pathways responsible for conversion of vascular smooth muscle cells into a chondrocyte-like cells promoting vascular calcification. We aim to identify the Fgfrs responsible for promoting vascular calcification in addition to the signaling pathways. The results from this proposal will offer avenues for new therapeutic targets to mitigate the effects of FGF23 on the cardiovascular system which will have a positive impact on the cardiovascular mortality/morbidity of patients with CKD/ESRD.