Mononuclear phagocytes in the pathogenesis of acute kidney injury

急性肾损伤(AKI)是内科和外科疾病的一种常见和严重的并发症 危重病人的显著可归因性发病率和死亡率。结果数据分析报告称 住院期间发生急性肾损伤的患者有发生慢性肾脏疾病的极大风险。 1年内患病。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，人们一直知道肾脏中存在着这种物质。他们积极参与维持肾脏的动态平衡。 而且，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 具有指导性假设，即AKI的过程和结果是特定因素参与的函数 MP的亚群，根据它们的胚胎起源和相关基因的表达来描述 巨噬细胞的功能与损伤后的时间有关。肾内常驻MP是唯一的F4/80HiCD11bInt 构成正常肾脏MP的50%的亚群，不同于单核细胞来源的MP 从外周循环到达。它们最初起源于胎儿的卵黄囊，定居在肾脏上。 在小鼠胚胎8.5-11天期间，在正常情况下很少或不接受来自循环的进一步输入 肾脏。肾MP的其他亚群来源于胎肝和胎骨中的造血干细胞 骨髓。目前对这些F4/80HiCD11bInt驻留肾MP在肾脏动态平衡中的作用知之甚少 和疾病。我们初步的批量和单细胞RNAseq数据、流式细胞仪分析和形态 研究表明，常驻肾MP遵循一个发育计划，包括一个发育阶段 切换常驻MP，例如开启主要组织相容性复合体(MHC)的表达 II级，出生后7-21天。值得注意的是，常驻肾MP恢复到MHC阴性。 AKI后不久的表型和初步的RNAseq数据表明常驻肾MP分泌Wnt 糖蛋白，已知与肾脏胚胎发育密切相关。这些发现 表明在受伤后至少有部分发育程序的重现，这已经是 之前提出过，但从未得到证实。我们的中心假设是肾居民MP经历了 至少部分在AKI之后重述的发展计划。这一发展计划是一项 伤后恢复机制的组成部分，并可能牵涉到重建失败 动态平衡(即不成功或错乱的修复)导致CKD。为了检验这一假设，我们将执行 以下具体目标：1)检验肾脏常驻MP是独立的、自我更新的假设 AKI后没有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向 CKD涉及驻留MP转录编程失败，无法返回到内环境平衡状态，导致 在肾病和纤维化基因产物的不适当表达。

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.