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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

基本信息

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
项目类别：
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

项目摘要

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）是一种常见的严重的内科和外科并发症