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Abstract: SA-PO110

Resident Macrophages Occupy Distinct Microenvironments in the Mouse and Human Kidney

Session Information

  • AKI: Mechanisms - III
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Cheung, Matthew David, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
  • Erman, Elise, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
  • Moore, Kyle H., The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
  • Ghajar-Rahimi, Gelare, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
  • Agarwal, Anupam, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
  • George, James F., The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
Background

Kidney resident macrophages (KRMs) are a unique, self-renewing F4/80HiCD11bInt population important for renal homeostasis and the response to acute kidney injury (AKI). Since they are present throughout the kidney tissue, which contains many distinct microenvironments, we hypothesized that subpopulations of KRMs are functionally diverse and location-specific. Here, we combined single-cell and spatial transcriptomics to characterize mouse and human KRM subpopulations during homeostasis and injury.

Methods

KRMs were isolated from C57BL/6J mice without treatment and after 19 min bilateral ischemia- reperfusion injury (BIRI) as well as from human kidneys from 2 kidney donors with creatinines of 0.9 and 2.5 mg/dL. We combined single-cell RNA sequencing (scRNAseq), spatial transcriptomics, flow cytometry, and immunofluorescence imaging to localize, characterize, and validate KRM populations during quiescence and following kidney injury in both mice and humans. scRNAseq and spatial gene expression data were analyzed using the R package, Seurat 4.0.

Results

scRNAseq and spatial transcriptomics revealed seven distinct KRM subpopulations in untreated mice that each reside within distinct zones associated with specific nephron structures. Each subpopulation was identifiable by a unique transcriptomic signature suggesting distinct functions. Specific protein markers were identified for several clusters allowing analysis by flow cytometry or immunofluorescence imaging. After injury, the localization of the KRM subpopulations change indicating either movement or changes in functional phenotypes. The pre-injury KRM topology is not fully restored for at least 28 days post-injury. Several human KRM subpopulations appear analogous to those of the mouse and also localize to specific regions.

Conclusion

KRMs consist of subpopulations organized into zones associated with nephron structures. The organization of these zones appear to change after function of injury, likely reflecting a differential response to the various damaged kidney structures. Similar subpopulations of KRMs were identified in the human kidney. Therefore, further study of the temporal and spatial characteristics and signaling pathways of these subpopulations in the context of homeostasis and injury is warranted.

Funding

  • NIDDK Support