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Regulation of FGF23 in Chronic Kidney Disease (CKD) by iron and inflammation

铁和炎症对慢性肾脏病 (CKD) 中 FGF23 的调节

基本信息

批准号：
9754113
负责人：
Nicolae Valentin David
金额：
$ 35.59万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2020-09-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9754113
关键词：
Binding Biological Blocking Antibodies Brucella abortus C-terminal Cardiovascular Diseases Cessation of life Chronic Chronic Kidney Failure Clinical Coupled Couples Data Data Reporting Diet Disease Progression Elements Enterobacteria phage P1 Cre recombinase Exposure to Genes Genetic Genetic Transcription Goals HIF1A gene Health Homeostasis Hormones Hypoxia Hypoxia Inducible Factor Inflammation Inflammatory Injury Injury to Kidney Interleukin-1 Iron Kidney Kidney Diseases Knockout Mice LCN2 gene Link Lipopolysaccharides Mediating Mediator of activation protein Metabolism Minerals Modeling Molecular Monoclonal Antibodies Mus Osteoblasts Osteocalcin Osteocytes Outcome Oxygen Pathway interactions Patients Pharmacology Phosphorus Production Proteins Recombinants Regulation Renal function Reporting Resistance Risk Role Serum Site-Directed Mutagenesis Stimulus System Testing Therapeutic Vitamin D Wild Type Mouse base bone bone cell chromatin immunoprecipitation clinically relevant cohort cytokine design fibroblast growth factor 23 genetic approach hypoxia inducible factor 1 improved improved outcome inhibitor/antagonist innovation inorganic phosphate insight interest iron deficiency mortality mouse model mutant novel novel therapeutic intervention overexpression promoter public health relevance response therapy design transcription factor

项目摘要

DESCRIPTION (provided by applicant): Fibroblast growth factor 23 (FGF23) is secreted by osteocytes and regulates phosphate and vitamin D homeostasis. Serum FGF23 levels rise early in the course of chronic kidney disease (CKD), and high levels are independently associated with greater risks of CKD progression, cardiovascular disease and death. These findings have stimulated interest in designing therapies to lower FGF23 levels, but the approach is limited by poor understanding of the molecular mechanisms that stimulate FGF23 production beginning in early CKD. Iron deficiency is a novel stimulator of FGF23 transcription and may be a critical contributor to elevated FGF23 levels in CKD. Although overt iron deficiency is uncommon in early CKD, functional iron deficiency due to reticuloendothelial iron sequestration as a result of chronic inflammation is highly prevalent. In preliminary data presented in this application, we demonstrate that high levels of the iron sequestering protein, neutrophil gelatinase associated lipocalin (NGAL), reduce intracellular iron concentrations in osteocytes and stimulate FGF23 production. In further preliminary data, we report that NGAL-mediated reductions in cellular iron stabilize hypoxia inducible factor (HIF)1a, which initiates FGF23 transcription by binding the FGF23 promoter. Since NGAL expression is increased in response to kidney injury and inflammation, and serum levels are chronically elevated in CKD, we propose that kidney injury stimulates NGAL production, which induces iron efflux from osteocytes, creating intracellular iron deficiency that stabilizes HIF1a and promotes FGF23 production. In this innovative proposal, we will examine the regulatory effects of inflammation, NGAL, and true and functional iron deficiency on FGF23 production in health and in CKD. In Aim 1, we will define the regulatory effects of inflammation and NGAL on FGF23 production by exposing wild type and NGALko mice to three models of systemic inflammation, and we will show that endogenous and exogenous NGAL increases FGF23 production. In Aim 2, we will investigate HIF1a as a molecular mediator of FGF23 regulation that underlies the mechanistic crosstalk between NGAL, iron, inflammation and FGF23. We will perform CHIP assays and site-directed mutagenesis to test whether HIF1a binds the FGF23 promoter, and we will delete HIF1a in osteocytes to demonstrate that HIF1aOc-cko mice are resistant to NGAL and iron deficiency-induced increases in FGF23. In Aim 3, we will determine the clinical relevance and therapeutic potential of the NGAL and HIF1a pathways in CKD by studying the impact of NGAL and HIF1a deletion in the Col4a3ko mouse model of progressive CKD. We will investigate if Col4a3ko/NGALko and Col4a3ko/HIF1aOc-cko compound mutants display blunted increases in FGF23 production relative to Col4a3ko mice with intact NGAL and HIF1a systems, and we will also test the effects on FGF23 production of NGAL blocking antibodies and HIF1 inhibitors in Col4a3ko mice. The project will contribute new insights into the molecular regulation of FGF23 in health and in CKD, and support our ultimate goal of developing novel therapeutic approaches to improve outcomes in CKD.

描述（由申请人提供）：成纤维细胞生长因子 23 (FGF23) 由骨细胞分泌，调节磷酸盐和维生素 D 稳态。血清 FGF23 水平在慢性肾脏病 (CKD) 病程早期就会升高，高水平与 CKD 进展、心血管疾病和死亡的更大风险独立相关。 These findings have stimulated interest in designing therapies to lower FGF23 levels, but the approach is limited by poor understanding of the molecular mechanisms that stimulate FGF23 production beginning in early CKD.缺铁是 FGF23 转录的新型刺激物，可能是 CKD 中 FGF23 水平升高的关键因素。尽管明显的缺铁在早期 CKD 中并不常见，但由于慢性炎症导致的网状内皮铁隔离而导致的功能性缺铁非常普遍。在本申请提供的初步数据中，我们证明高水平的铁螯合蛋白、中性粒细胞明胶酶相关脂质运载蛋白（NGAL）可降低骨细胞中的细胞内铁浓度并刺激 FGF23 的产生。在进一步的初步数据中，我们报告了 NGAL 介导的细胞铁减少稳定了缺氧诱导因子 (HIF)1a，该因子通过结合 FGF23 启动子来启动 FGF23 转录。由于 NGAL 表达因肾损伤和炎症而增加，并且 CKD 患者血清水平长期升高，因此我们认为肾损伤刺激 NGAL 产生，从而诱导铁从骨细胞流出，造成细胞内铁缺乏，从而稳定 HIF1a 并促进 FGF23 产生。在这项创新提案中，我们将研究炎症、NGAL 以及真正的功能性缺铁对健康和 CKD 中 FGF23 产生的调节作用。在目标 1 中，我们将通过将野生型和 NGALko 小鼠暴露于三种全身炎症模型来定义炎症和 NGAL 对 FGF23 产生的调节作用，并且我们将证明内源性和外源性 NGAL 会增加 FGF23 的产生。在目标 2 中，我们将研究 HIF1a 作为 FGF23 调节的分子介质，是 NGAL、铁、炎症和 FGF23 之间机制串扰的基础。 We will perform CHIP assays and site-directed mutagenesis to test whether HIF1a binds the FGF23 promoter, and we will delete HIF1a in osteocytes to demonstrate that HIF1aOc-cko mice are resistant to NGAL and iron deficiency-induced increases in FGF23.在目标 3 中，我们将通过研究 NGAL 和 HIF1a 缺失对进行性 CKD 的 Col4a3ko 小鼠模型的影响，确定 NGAL 和 HIF1a 通路在 CKD 中的临床相关性和治疗潜力。我们将研究与具有完整 NGAL 和 HIF1a 系统的 Col4a3ko 小鼠相比，Col4a3ko/NGALko 和 Col4a3ko/HIF1aOc-cko 复合突变体是否表现出 FGF23 产量增加减弱，并且我们还将测试 NGAL 阻断抗体和 HIF1 抑制剂对 Col4a3ko 小鼠中 FGF23 产量的影响。 The project will contribute new insights into the molecular regulation of FGF23 in health and in CKD, and support our ultimate goal of developing novel therapeutic approaches to improve outcomes in CKD.