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.
Acute kidney injury (AKI) is a major health problem for hospitalized patients, especially those in intensive care units where mortality among such patients can be as high as 80%. The studies described in this proposal will investigate the role of renal mononuclear phagocytes, which have been known to exist within the kidney for nearly 40 years, but have only recently been determined to play a role in AKI and normal kidney function. We will determine the origin and function of these cells in the kidney and the roles that they play in the initial injury and the repair processes after AKI.
