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: 10320001
• 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/10320001
• 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（AKI）是内科和外科疾病常见且严重的并发症， 危重患者的显着发病率和死亡率。结果数据分析表明 住院期间发生 AKI 的患者存在发生慢性肾病的巨大风险 1年内患病。单核吞噬细胞（MP）由巨噬细胞和树突状细胞组成，具有 长期以来人们就知道它存在于肾脏内。他们积极参与维持肾脏稳态 更重要的是，受伤后体内平衡的恢复。我们建议研究 MP 在 AKI 中的作用 指导性假设是 AKI 的过程和结果是特定参与因素的函数 MP亚群，根据其胚胎起源和相关基因的表达来划分 与损伤后时间相关的巨噬细胞功能。肾内驻留 MP 是独特的 F4/80HiCD11bInt 构成正常肾脏中肾 MP 50% 的亚群，与单核细胞来源的 MP 不同 来自末梢循环。它们最初来自胎儿卵黄囊，定居在肾脏 在小鼠的胚胎期 8.5-11 天内，正常情况下几乎不接受来自循环的进一步输入 肾脏。肾 MP 的其他亚群源自胎儿肝脏和骨骼中的造血干细胞 骨髓。关于这些 F4/80HiCD11bInt 常驻肾 MP 在肾脏稳态中的作用知之甚少 和疾病。我们的初步批量和单细胞 RNAseq 数据、流式细胞术分析和形态学分析 研究表明，常驻肾 MP 遵循一个发育计划，其中包括发育 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 出生后 7-21 天之间为 II 级。值得注意的是，常驻肾 MP 逆转为 MHC 阴性 AKI 后不久的表型和初步 RNAseq 数据表明驻留肾 MP 分泌 Wnt 糖蛋白，已知与肾胚胎发育密切相关。这些发现 表明受伤后至少有部分发展计划的重现，这已被证实 以前提出过，但从未得到证实。我们的中心假设是肾驻留 MP 经历了 AKI 后至少部分概括的发展计划。这个发展计划是一个 损伤恢复机制的组成部分，可能与重建失败有关 体内平衡（即修复不成功或紊乱）导致 CKD。为了检验这个假设，我们将执行 以下具体目标：1）检验肾驻留 MP 是独立的、自我更新的假设 AKI 后不接受外周循环输入的亚群； 2）检验假设 肾 MP 概括了 AKI 后的发育程序； 3) 检验 AKI 转变为 CKD 涉及驻留 MP 转录编程未能返回稳态，导致 肾生成和纤维生成基因产物的不适当表达。