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Abstract: FR-PO969

Resident Memory T Cells in Aristolochic Acid-Induced CKD

Session Information

  • CKD: Pathobiology - I
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms

Authors

  • Moore, Kyle H., The University of Alabama at Birmingham Division of Nephrology, Birmingham, Alabama, United States
  • Erman, Elise, 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
  • George, James F., 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
Background

Chronic Kidney Disease (CKD) is a significant health burden affecting millions of Americans. No current therapeutics can halt or reverse the progression of CKD. The immune system, inflammation, and fibrosis are known to be involved in the progression of CKD, but specific contributions of T cells and how they become involved in the pathophysiological process remain poorly understood.

Methods

Mice were injected with 2mg aristolochic acid (AA) per kg body weight i.p. (saline control) for five consecutive days to induce a prolonged decline in kidney function. Glomerular filtration rates (GFRs) were measured using FITC-sinistrin clearance at baseline before injury, and at one day, two weeks, four weeks, and six weeks after their first AA injection. Blood was collected and kidneys were harvested and processed for flow cytometry, imaging, and single cell RNA sequencing. Serum creatinine (SCr) was measured using LC-MSMS.

Results

There were no signs of acute injury one day post-injection, but by two weeks, AA mice had reduced GFR and increased SCr. At six weeks GFRs of AA mice remained low compared to controls (114 mL/min vs 220 mL/min, respectively), and SCr remained elevated (0.29 mg/dL AA vs 0.09 mg/dL Vehicle). The numbers of intrarenal CD45+ cells, CD4+ T cells, and CD8+ T cells were significantly elevated at two, four, and six weeks post-injury. Interestingly, CD103+ resident memory T cells (TRMs) expanded to represent 54% of the CD8+ and 36% of the CD4+ populations (7% and 3% in controls). CD8+ TRMs had increased expression of GZMB and PRF1. At six weeks there were also histological signs of interstitial fibrosis and tubular atrophy.

Conclusion

There was sustained impairment of kidney function in animals treated with AA, as indicated by reduced GFR and increased SCr at least six weeks after injury. There was also a sustained increase in CD4+ and CD8+ T cells with a large expansion of TRMs expressing apoptotic cytokines. TRMs have been recently characterized as non-circulating immune cells that contribute to chronic inflammation and, based on our findings, may contribute to inflammation in CKD. Future studies will aim to fully describe the cytokine profile of kidney TRMs in order to determine their role in tubular apoptosis and interstitial fibrosis.

Funding

  • NIDDK Support