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Kidney Week

Abstract: FR-OR16

Kidney Resident Macrophages Alter MHC II Expression and Location in Response to Acute and Chronic Injury

Session Information

  • AKI Research: Mechanisms
    November 04, 2022 | Location: W230, Orange County Convention Center‚ West Building
    Abstract Time: 05:15 PM - 05:24 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Erman, Elise, The University of Alabama at Birmingham Department of Surgery, Birmingham, Alabama, United States
  • Moore, Kyle H., The University of Alabama at Birmingham Department of Surgery, Birmingham, Alabama, United States
  • Cheung, Matthew David, The University of Alabama at Birmingham Department of Surgery, Birmingham, Alabama, United States
  • Agarwal, Anupam, The University of Alabama at Birmingham Division of Nephrology, Birmingham, Alabama, United States
  • George, James F., The University of Alabama at Birmingham Department of Surgery, Birmingham, Alabama, United States
Background

Patients remain at increased risk for developing chronic kidney disease (CKD) after recovery from AKI. The cause of this increased risk is unknown and biomarkers for it are severely lacking. We have identified a subpopulation of kidney injury-associated macrophages (KIA) that appear after AKI and lack MHC II expression. We hypothesize that KIA cells are uniquely involved in the pathogenesis of injury and may be a key to an AKI to CKD transition.

Methods

C57BL/6J mice (n=6/grp) were subjected to a bilateral ischemia-reperfusion injury (AKI) or aristolochic acid treatment at doses of 2 mg/kg BW (CKD) or 3 mg/kg BW (severe CKD). KIA cells were localized within the tissue using Visium Spatial Transcriptomics and single-cell RNA sequencing (scRNAseq). The phenotype was validated by flow cytometry. Kidney function was determined using serum creatinine and glomerular filtration rate (GFR).

Results

Following AKI, KIA cells are detectable at 24 hours by flow cytometry and at 12 hours by scRNAseq. Spatial transcriptomics shows that KIA cells localize to the cortico-medullary region contiguous with the proximal tubule S3 segments. Differentially expressed genes include those associated with platelets and wound healing. As kidney function recovers, KIA cells decrease in number and return to quiescent levels by 14 days post-injury (p < 0.0001). In contrast, in the severe CKD model, KIA cells persist for up to six weeks, composing approximately 20% of the total kidney resident macrophage population (p = 0.0035). A less severe version of CKD results in fewer KIA cells but similar persistence, suggesting the appearance of KIA cells directly correlates with injury severity. Following a low dose of LPS, KIA cells represent up to 90% of the resident compartment without a significant increase in serum creatinine (p < 0.0001).

Conclusion

We conclude that KIA cells may locate at damage sites and may be involved in the AKI to CKD transition. Therefore, targeting KIA cells could potentially reduce CKD risk following AKI.