Mononuclear phagocytes in the pathogenesis of acute kidney injury

单核吞噬细胞在急性肾损伤发病机制中的作用

• 批准号: 9888371
• 负责人: ANUPAM AGARWAL
• 金额: $ 45.66万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9888371
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Birth; Blood Circulation; Bone Marrow; Cell Cycle; Cell physiology; Chronic Kidney Failure; Clinical Trials; Critical Illness; Data; Data Discovery; Data Reporting; Dendritic Cells; Development; Dialysis procedure; Disease; Disease model; Embryo; Embryonic Development; Event; Failure; Fetal Liver; Flow Cytometry; Gene Expression; Gene Expression Profile; Genetic Transcription; Glycoproteins; Goals; Growth; Health; Health Care Costs; Hematopoietic stem cells; Histocompatibility Antigens Class II; Homeostasis; Hospitalization; Impairment; Injury; Injury to Kidney; Intensive Care Units; Kidney; Knowledge; Laboratories; Length of Stay; Life; Link; Maintenance; Major Histocompatibility Complex; Modality; Mononuclear; Morbidity - disease rate; Morphology; Mus; Operative Surgical Procedures; Outcome; Parabiosis; Pathogenesis; Pathway interactions; Patients; Peripheral; Phagocytes; Phenotype; Platelet-Derived Growth Factor; Play; Population; Process; Recovery; Renal Replacement Therapy; Renal function; Risk; Role; Supportive care; Surface; Techniques; Testing; Therapeutic Intervention; Time; Tissues; Yolk Sac; experimental study; fetal; gene discovery; gene product; injury and repair; injury recovery; macrophage; medical complication; monocyte; mortality; next generation sequencing; novel; peripheral blood; programs; repaired; restoration; self-renewal; single-cell RNA sequencing; transcriptome sequencing

Acute kidney injury (AKI) is a common and serious complication of medical and surgical diseases that has significant attributable morbidity and mortality in critically ill patients. Analysis of outcomes data reported that patients who develop AKI during a hospitalization are at substantial risk for the development of chronic kidney disease within 1 year. Mononuclear phagocytes (MP), which consist of macrophages and dendritic cells, have long been known to exist within the kidney. They are actively involved in maintenance of renal homeostasis and, more importantly, the restoration of homeostasis after injury. We propose to study the role of MP in AKI with the guiding hypothesis that the course and outcome of AKI is a function of the involvement of specific subpopulations of MP, delineated on the basis of their embryonic origin and expression of genes associated with macrophage function with respect to time post-injury. Intrarenal resident MP are a unique F4/80HiCD11bInt subpopulation that constitute 50% of renal MP in normal kidneys and are distinct from monocyte derived MP that arrive from the peripheral circulation. They initially arise from the fetal yolk sac, colonizing the kidney during embryonic days 8.5-11 in mice and receive little to no further input from the circulation in normal kidneys. Other subpopulations of renal MP arise from hematopoietic stem cells in the fetal liver and bone marrow. Very little is known about the role of these F4/80HiCD11bInt resident renal MP in kidney homeostasis and disease. Our preliminary bulk and single cell RNAseq data, flow cytometry analyses and morphological studies indicate that resident renal MP follow a developmental program which encompasses a developmental switch in the resident MP, exemplified by turning on expression of major histocompatibility complex (MHC) class II between 7-21 days after birth. Notably, there is a reversion of resident renal MP to the MHC negative phenotype shortly after AKI and preliminary RNAseq data indicate that resident renal MP secrete Wnt glycoproteins, which are known to be intimately involved with kidney embryonic development. These findings suggest there is at least partial recapitulation of a developmental program after injury, which has been previously proposed, but never proven. Our central hypothesis is that renal resident MP undergo a developmental program that is recapitulated, at least in part, following AKI. This developmental program is a component of the mechanism of recovery from injury and could be involved in a failure to re-establish homeostasis (i.e. unsuccessful or deranged repair) leading to CKD. To test this hypothesis, we will execute the following specific aims: 1) To test the hypothesis that renal resident MP are an independent, self-renewing subpopulation that receives no input from the peripheral circulation after AKI; 2) To test the hypothesis that renal MP recapitulate a developmental program after AKI; 3) To test the hypothesis that the transition of AKI to CKD involves a failure of resident MP transcriptional programming to return to the homeostatic state, resulting in inappropriate expression of nephrogenic and fibrogenic gene products.

急性肾损伤（阿基）是内科和外科疾病的常见且严重的并发症， 危重患者的显著归因发病率和死亡率。结果数据分析报告称， 在住院期间发生阿基的患者具有发生慢性肾脏病的显著风险， 一年内发病。单核巨噬细胞（MP），由巨噬细胞和树突状细胞组成，具有 长期以来一直存在于肾脏中。它们积极参与维持肾内稳态 更重要的是，恢复受伤后的体内平衡。我们建议研究MP在阿基中的作用， 阿基的过程和结果是特定的参与的函数， MP的亚群，根据其胚胎起源和相关基因的表达进行描述 巨噬细胞功能与损伤后时间的关系。肾内驻留MP是一种独特的F4/80 HiCD 11bInt 在正常肾脏中占肾MP 50%且不同于单核细胞衍生MP亚群 来自外周循环的血液它们最初起源于胚胎卵黄囊，在肾脏定植 在小鼠的胚胎期8.5-11天期间， 肾脏其他的肾MP亚群来源于胎儿肝脏和骨骼中的造血干细胞 骨髓关于这些F4/80 HiCD 11bInt常驻肾MP在肾内稳态中的作用知之甚少 和疾病我们初步的批量和单细胞RNAseq数据，流式细胞术分析和形态学分析， 研究表明，居民肾MP遵循一个发展计划，其中包括发展 常驻MP中的开关，例如打开主要组织相容性复合体（MHC）的表达 II类，出生后7-21天。值得注意的是，有一个逆转的居民肾MP的MHC阴性 阿基后不久表型和初步RNAseq数据表明，常驻肾MP分泌Wnt 糖蛋白，这是已知的密切参与肾脏胚胎发育。这些发现 这表明，至少有一个受伤后的发展计划，这已经部分重演， 以前提出过，但从未被证实。我们的中心假设是，肾居民MP经历了一个 在阿基之后，至少部分地概括了发展计划。这个发展计划是一个 损伤恢复机制的组成部分，并可能参与重建失败 稳态（即不成功或紊乱的修复）导致CKD。为了验证这个假设，我们将执行 以下具体目的：1）验证肾驻留MP是一种独立的、自我更新的 阿基后不接受外周循环输入的亚群; 2）为了检验以下假设， 肾MP概括了阿基后的发育程序; 3）为了检验阿基向MP转变的假设， CKD涉及常驻MP转录编程返回稳态的失败，导致 肾原性和纤维原性基因产物的不适当表达。