Abstract
Acute kidney injury (AKI) is a devastating clinical condition affecting at least two-thirds of critically ill patients, and, among these patients, it is associated with a greater than 60% risk of mortality. Kidney mononuclear phagocytes (MPs) are implicated in pathogenesis and healing in mouse models of AKI and, thus, have been the subject of investigation as potential targets for clinical intervention. We have determined that, after injury, F4/80hi-expressing kidney-resident macrophages (KRMs) are a distinct cellular subpopulation that does not differentiate from nonresident infiltrating MPs. However, if KRMs are depleted using polyinosinic/polycytidylic acid (poly I:C), they can be reconstituted from bone marrow–derived precursors. Further, KRMs lack major histocompatibility complex class II (MHCII) expression before P7 but upregulate it over the next 14 days. This MHCII– KRM phenotype reappears after injury. RNA sequencing shows that injury causes transcriptional reprogramming of KRMs such that they more closely resemble that found at P7. KRMs after injury are also enriched in Wingless-type MMTV integration site family (Wnt) signaling, indicating that a pathway vital for mouse and human kidney development is active. These data indicate that mechanisms involved in kidney development may be functioning after injury in KRMs.
Authors
Jeremie M. Lever, Travis D. Hull, Ravindra Boddu, Mark E. Pepin, Laurence M. Black, Oreoluwa O. Adedoyin, Zhengqin Yang, Amie M. Traylor, Yanlin Jiang, Zhang Li, Jacelyn E. Peabody, Hannah E. Eckenrode, David K. Crossman, Michael R. Crowley, Subhashini Bolisetty, Kurt A. Zimmerman, Adam R. Wende, Michal Mrug, Bradley K. Yoder, Anupam Agarwal, James F. George
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