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.

项目摘要 完整成纤维细胞生长因子23（iFGF 23）是由骨分泌的磷酸调节激素。慢性 肾脏疾病（CKD），Fgf 23转录增加与心血管死亡率相关，铁干扰 代谢和贫血。Fgf 23转录在生理学上与FGF 23被弗林蛋白酶切割偶联，导致FGF 23的转录。 iFGF 23、羧基末端（Cter）和氨基末端（Nter）FGF 23肽的分泌。的既定 iFGF 23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FGF 23靶点的证据，这可能是Cter和Nter-FGF 23增加的结果 发信号。迫切需要减少CKD中FGF 23相关不良结局的新方法 但由于缺乏对FGF 23肽的作用的了解，目前的疗法是次优的。 在初步数据中，我们表明，除了iFGF 23，FGF 23肽分泌的骨和骨外， 来源，包括红系细胞。我们还表明，这些肽显示新的生理 功能协调发展的Cter-FGF 23肽抑制肝铁调节激素铁调素的分泌， 增加循环铁。当FGF 23表达时，Nter-FGF 23肽不在循环中释放 但在缺铁动物、CKD患者和小鼠中， 有助于增加循环Nter-FGF 23水平。当升高时，Nter-FGF 23减少了Nter-FGF 23的分泌。 促红细胞生成素抑制红细胞生成并诱导左心室肥大（LVH）。这些观察结果支持 FGF 23肽的重要新作用，以及Fgf 23转录偶联调节的功能作用 和iFGF 23切割。在目的1中，我们将建立Cter-FGF 23肽的生理和病理作用， 在铁代谢中。使用多种遗传小鼠模型，我们将删除和过表达Fgf 23和Cter-Fgf 23， 在骨中，为了测试由增加的FGF 23切割产生的Cter-FGF 23肽是否保护小鼠免受 通过在高（炎症和铁过载）或低铁血症模型中独特地限制铁调素分泌而引起明显的低铁血症。 低（铁缺乏）内源性铁调素，并将这些作用与外源性铁调素施用进行比较。我们 将进一步测试两个国家的遗传和药理学Cter-FGF 23补充剂的治疗潜力， 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 FGF 23和Nter-FGF 23在骨细胞中的遗传过表达和药理学给药， 在体内和体外研究iFGF 23、Nter-FGF 23和FGFR信号传导在红系细胞中的直接作用。 红细胞生成的抑制，以及它们通过调节肾脏中红细胞生成素（EPO）的产生而发挥的间接作用， 肝脏我们将进一步研究红系细胞产生的Nter-FGF 23肽是否有助于患有LVH的小鼠的LVH。 CKD，并测试Nter-FGF 23在心肌细胞培养物中的直接肥大作用。该项目将 有助于对FGF 23的分子功能有新的认识，并支持我们的最终目标， 新的治疗方法，以改善与过量FGF 23相关的不良结果。