Role of FGF23 peptides in chronic kidney disease (CKD)

项目总结 完整成纤维细胞生长因子23(IFGF23)是一种由骨骼分泌的磷酸调节激素。在慢性病 肾脏疾病(CKD)，FGF23转录增加与心血管死亡、铁紊乱有关 新陈代谢和贫血。FGF23转录在生理上与FGF23被Furin切割偶联，导致 分泌iFGF23、羧基末端(CTER)和氨基末端(NTER)FGF23多肽。久负盛名 IFGF23的功能是通过靶向肾脏来维持正常的磷酸盐稳态，但目前正在出现 支持肾外FGF23靶点的证据可能是Cter-和Enter-FGF23增加的结果 发信号。迫切需要新的方法来减少慢性肾脏病中FGF23相关的不良后果 但由于缺乏对FGF23多肽作用的了解，目前的治疗方法并不理想。 在初步数据中，我们发现除了iFGF23外，FGF23多肽还由骨和骨外分泌。 CKD的来源，包括红系细胞。我们还表明，这些多肽显示出新的生理活性。 功能。CTER-FGF23肽抑制肝铁调节激素海普西丁的分泌 增加循环中的铁。当表达FGF23时，Enter-FGF23肽不会在循环中释放 在骨骼中，但在缺铁动物、CKD患者和小鼠中，FGF23由红系细胞产生 有助于增加循环中的nter-FGF23水平。当升高时，nter-FGF23减少了 促红细胞生成素，抑制红细胞生成并诱导左心室肥厚。这些观察结果支持 FGF23多肽的重要新功能及其在FGF23转录偶联调控中的作用 和iFGF23裂解。在目标1中，我们将确定cter-fgf23多肽的生理和病理作用。 在铁的新陈代谢。利用多种遗传小鼠模型，我们将删除和过度表达FGF23和Cter-FGF23 在骨骼中，为了测试由于FGF23裂解增加而产生的Cter-FGF23肽是否能保护小鼠免受 通过独特地限制高(炎症和铁负荷)或高铁血症模型中海普西丁的分泌来显性低铁血症 低(缺铁)内源性海普西丁，并将这些效果与外源性海普西丁给药进行比较。我们 将进一步测试遗传和药理学补充剂Cter-FGF23在两个方面的治疗潜力 建立CKD小鼠模型，评估缺铁性贫血的发生和发展。在目标2中，我们将使用 FGF23和Enter-FGF23在骨细胞和骨组织中的遗传过表达及药物作用 体内和体外研究iFGF23、nter-FGF23和FGFR信号在红系细胞中的直接作用 促红细胞生成素(EPO)的抑制作用及其在肾脏和肾脏中的间接作用 肝脏。我们将进一步研究红系产生的Nter-FGF23多肽是否对小鼠左室肥厚起作用。 并检测Enter-FGF23对培养心肌细胞的直接肥大作用。这个项目将 有助于对FGF23分子功能的新见解，并支持我们开发 新的治疗方法，以改善与过量FGF23相关的不良结果。

PROJECT SUMMARY Intact fibroblast growth factor 23 (iFGF23) is a phosphate regulating hormone secreted by bone. In chronic kidney disease (CKD), increased Fgf23 transcription is associated with cardiovascular mortality, disturbed iron metabolism and anemia. Fgf23 transcription is physiologically coupled to FGF23 cleavage by Furin resulting in secretion of iFGF23, carboxy terminal (Cter) and amino terminal (Nter) FGF23 peptides. The well-established function of iFGF23 is to maintain normal phosphate homeostasis by targeting the kidney but there is emerging evidence supporting extra-renal FGF23 targets which might be the result of increased Cter- and Nter-FGF23 signaling. Novel approaches to reduce FGF23-associated adverse outcomes in CKD are desperately needed but current therapies are suboptimal due to lack of understanding of the role of FGF23 peptides. In preliminary data we show that in addition to iFGF23, FGF23 peptides are secreted by bone and extraosseous sources, including erythroid cells, in CKD. We also show that these peptides display novel physiological functions. Cter-FGF23 peptides suppress the secretion of the hepatic iron regulatory hormone, hepcidin, leading to increased circulating iron. Nter-FGF23 peptides are not released in the circulation when FGF23 is expressed in bone, but in iron deficient animals and patients and mice with CKD, FGF23 production by erythroid cells contribute to increased circulating Nter-FGF23 levels. When elevated, Nter-FGF23 reduces the secretion of erythropoietin, inhibits erythropoiesis and induces left ventricular hypertrophy (LVH). These observations support important new roles of FGF23 peptides, and a functional role for the coupled regulation of Fgf23 transcription and iFGF23 cleavage. In Aim 1, we will establish the physiological and pathological role of Cter-FGF23 peptides in iron metabolism. Using multiple genetic mouse models, we will delete and overexpress Fgf23 and Cter-Fgf23 in bone, to test whether Cter-FGF23 peptides generated from increased FGF23 cleavage, protect mice against overt hypoferremia by uniquely limiting hepcidin secretion in models of high (inflammation and iron overload) or low (iron deficiency) endogenous hepcidin and compare these effects to exogenous hepcidin administration. We will further test the therapeutic potential of genetic and pharmacologic Cter-FGF23 supplementation in two mouse models of CKD and assess the onset and development of iron deficiency anemia. In Aim 2, we will use the genetic overexpression and pharmacologic administration of FGF23 and Nter-FGF23 in osteocytes and erythroid cells, in vivo and in vitro, to investigate the direct role of iFGF23, Nter-FGF23 and FGFR signaling in the inhibition of erythropoiesis, and their indirect role by regulating erythropoietin (EPO) production in kidney and liver. We will further investigate whether erythroid-produced Nter-FGF23 peptides contribute to LVH in mice with CKD and test the direct hypertrophic effects of Nter-FGF23 in cardiomyocytes cultures. This project will contribute to new insights into the molecular functions of FGF23 and support our ultimate goal of developing novel therapeutic approaches to improve adverse outcomes associated with excess FGF23.