Role of FGF23 peptides in chronic kidney disease (CKD)

FGF23 肽在慢性肾脏病 (CKD) 中的作用

• 批准号: 10586788
• 负责人: Nicolae Valentin David
• 金额: $ 63.61万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586788
• 关键词: Acute; Anemia; Animals; Bilateral; Binding; Biological Availability; Brucella abortus; C-terminal; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cell Differentiation process; Cell Maturation; Cell secretion; Chronic; Chronic Kidney Failure; Circulation; Consensus; Coupled; Coupling; Data; Development; Diet; Disease; Disease Outcome; Disease model; Erythroid; Erythroid Cells; Erythropoiesis; Erythropoietin; Fibroblast Growth Factor Receptors; General Population; Genetic; Genetic Transcription; Goals; Heart Hypertrophy; Hepatic; Hepatocyte; Homeostasis; Hormone secretion; Hormones; Impairment; In Vitro; Inflammation; Inflammatory; Interleukins; Iron; Iron Overload; Iron deficiency anemia; Kidney; Lead; Left Ventricular Hypertrophy; Length; Liver; Mediating; Metabolism; Modeling; Molecular; Morphology; Mus; Muscle Cells; N-terminal; Operative Surgical Procedures; Osteoblasts; Osteocytes; Outcome; Pathologic; Patients; Peptides; Physiological; Production; Proteins; Regulation; Renal function; Reperfusion Injury; Resistance; Role; Signal Transduction; Slice; Source; Supplementation; Surgical Models; Testing; Therapeutic; Ventricular; adverse outcome; bone; dentin matrix protein 1; design; erythroid differentiation; fibroblast growth factor 23; hepcidin; improved; improved outcome; in vivo; innovation; inorganic phosphate; insight; iron deficiency; iron metabolism; mortality; mouse model; neonatal mice; new therapeutic target; novel; novel strategies; novel therapeutic intervention; overexpression; pharmacologic; prevent; response; therapeutic evaluation

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.

项目概要 完整成纤维细胞生长因子 23 (iFGF23) 是骨分泌的磷酸盐调节激素。在慢性 肾脏疾病 (CKD)、Fgf23 转录增加与心血管死亡率相关、铁质紊乱 新陈代谢和贫血。 Fgf23 转录在生理上与弗林蛋白酶 (Furin) 裂解 FGF23 耦合，从而导致 iFGF23、羧基末端 (Cter) 和氨基末端 (Nter) FGF23 肽的分泌。完善的 iFGF23 的功能是通过靶向肾脏来维持正常的磷酸盐稳态，但新出现的 支持肾外 FGF23 目标的证据，这可能是 Cter- 和 Nter-FGF23 增加的结果 发信号。迫切需要减少 CKD 中 FGF23 相关不良后果的新方法 但由于缺乏对 FGF23 肽作用的了解，目前的疗法并不理想。 初步数据表明，除了 iFGF23 之外，骨和骨外也分泌 FGF23 肽。 CKD 中的来源，包括红细胞。我们还表明这些肽表现出新颖的生理功能 功能。 Cter-FGF23 肽抑制肝铁调节激素铁调素的分泌，导致 增加循环铁。当 FGF23 表达时，Nter-FGF23 肽不会释放到循环中 在骨骼中，但在缺铁动物以及患有 CKD 的患者和小鼠中，红细胞细胞会产生 FGF23 有助于增加循环 Nter-FGF23 水平。当 Nter-FGF23 升高时，会减少 促红细胞生成素，抑制红细胞生成并诱导左心室肥厚（LVH）。这些观察结果支持 FGF23肽的重要新作用以及Fgf23转录耦合调节的功能作用 和 iFGF23 裂解。在目标 1 中，我们将确定 Cter-FGF23 肽的生理和病理作用 在铁代谢中。使用多个基因小鼠模型，我们将删除并过度表达 Fgf23 和 Cter-Fgf23 在骨骼中，测试 FGF23 裂解增加产生的 Cter-FGF23 肽是否可以保护小鼠免受 通过独特地限制高（炎症和铁超载）模型中的铁调素分泌来明显的低铁血症或 低（缺铁）内源性铁调素，并将这些效果与外源性铁调素给药进行比较。我们 将进一步测试两种情况下补充 Cter-FGF23 的遗传和药理学治疗潜力 CKD 小鼠模型并评估缺铁性贫血的发生和发展。在目标 2 中，我们将使用 骨细胞中 FGF23 和 Nter-FGF23 的基因过表达和药理学施用 在体内和体外对红系细胞进行研究，研究 iFGF23、Nter-FGF23 和 FGFR 信号传导在 红细胞生成的抑制及其通过调节肾脏和肾脏中促红细胞生成素 (EPO) 产生的间接作用 肝。我们将进一步研究红系产生的 Nter-FGF23 肽是否有助于患有 LVH 的小鼠 CKD 并测试 Nter-FGF23 在心肌细胞培养物中的直接肥大作用。该项目将 有助于对 FGF23 分子功能的新见解，并支持我们开发的最终目标 改善与过量 FGF23 相关的不良后果的新治疗方法。