Regulation of Macrophage Phenotype by Ferritin Heavy Chain in CKD

摘要 慢性肾脏疾病(CKD)是一个世界性的公共卫生问题，影响着约8.5亿人，其中包括37 百万美国人。晚期慢性肾脏病导致许多不良的临床结局，导致高发病率 死亡率、发病率和医疗保健支出。认识到这些令人震惊的挑战，该部 卫生与公众服务部通过执行机构发起“促进美国肾脏健康(AAKH)” 2019年7月订购。铁代谢紊乱是晚期CKD的一个标志，然而， 这种扰动的机制基础及其对慢性肾脏病病程的临床影响尚不完全。 明白了。该项目的总体目标是填补目前知识上的空白，解决这一未得到满足的需求 以铁代谢为靶点减缓慢性肾脏病进展的新型治疗干预措施的开发 以及推迟肾脏替代疗法的需要，这是AAKH倡议的两个主要目标。通过 在进行初步研究时，我们发现巨噬细胞铁蛋白重链(FTH)减少 慢性肾脏病的发展和进展。在我们发现的指导下，我们提出了一个统一的假设，即髓系 FTH在损伤/炎症条件下协调铁的分布并调节巨噬细胞的可塑性。 这一前提通过(I)Spic的显著上调而得到证实，Spic是一种定义谱系的转录因子， 选择性地控制铁循环巨噬细胞的发育和(Ii)显著升高和聚集 突触核蛋白-α(SNCA)，一种常见的神经退行性变条件下的促炎因子，在两种动物模型中 在髓系FTH靶向缺失小鼠肾脏中观察到显著高水平的CKD 车厢。为了证实我们的假设，我们将执行以下具体目标：目标1：测试 髓系促甲状腺激素通过调节单核细胞/M细胞Φ向铁循环表型分化的假说 控制转录因子Spic。目的2：检验髓系FTH建立疾病的假设 通过抑制SNCA对CKD的耐受。成功完成拟议的目标将对 对我们理解髓系FTH、SpIC和SNCA表达的个体和集体效应的影响 通过肾脏对铁的处理及其在CKD发病机制中的具体内涵作用，从而为 通过靶向CKD的铁代谢，为这种疾病的新治疗方法提供了途径。

Abstract Chronic kidney disease (CKD) is a worldwide public health problem affecting ~850 million people including 37 million Americans. Advanced CKD results in a number of adverse clinical outcomes leading to high rates of mortality, morbidity, and healthcare expenditure. Recognizing these staggering challenges, the Department of Health and Human Services initiated the “Advancing American Kidney Health (AAKH)” through Executive Order in July 2019. Derangements in iron metabolism are a hallmark of advanced CKD, however, the mechanistic underpinnings of such perturbations and their clinical impact on the course of CKD are not fully understood. The overall goal of this project is to fill the current gaps in knowledge and address this unmet need for the development of novel therapeutic interventions by targeting iron metabolism to slow progression of CKD and delay the need for kidney replacement therapy, two of the major goals of the AAKH initiative. By conducting preliminary studies, we have discovered that macrophage ferritin heavy chain (FtH) diminishes development and progression of CKD. Guided by our findings we propose the unifying hypothesis that myeloid FtH orchestrates iron distribution and regulates macrophage plasticity under injurious/inflammatory conditions. This premise is substantiated by (i) significant upregulation of Spic, a lineage-defining transcription factor that selectively controls development of iron recycling macrophages and (ii) marked elevation and aggregation of synuclein-alpha (Snca), a common pro-inflammatory factor in neurodegenerative conditions in in two models of CKD with substantially higher levels observed in kidneys of mice with targeted deletion of FtH in myeloid compartment. To confirm our hypothesis, we will execute the following specific aims: Aim 1: To test the hypothesis that myeloid FtH regulates monocyte/MΦ differentiation towards iron recycling phenotype through controlling transcription factor Spic. Aim 2: To test the hypothesis that myeloid FtH establishes disease tolerance to CKD via suppression of Snca. Successful completion of the proposed aims will have a significant impact on our understanding of the individual and collective effects of myeloid FtH, Spic and Snca expression in iron handling by the kidney and their detailed connotative roles in the pathogenesis of CKD, thereby paving the way for a new therapeutic approach in this disease by targeting iron metabolism in CKD.