Abstract: FR-PO359

Lymphocytes and PD-1 in Aristolochic Acid Nephropathy

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Kinsey, Gilbert R., Univerisity of Virginia, Charlottesville, Virginia, United States
  • Stevens, Brian K., Univerisity of Virginia, Charlottesville, Virginia, United States
  • Yang, Mana, Univerisity of Virginia, Charlottesville, Virginia, United States
Background

Aristolochic acid is a nephrotoxic agent previously used in traditional Chinese medicine and found as an adulterant in some herbal supplements. Clinical studies have revealed extensive inflammation in kidneys of patients with aristolochic acid nephropathy (AAN). AAN involves an acute toxic injury to tubular epithelial cells that leads to immune cell infiltration and progressive fibrosis over time. Programmed death 1 (PD-1) is a co-stimulatory molecule that limits the activation of T cells and lymphocytes have important roles in other forms of kidney injury, but their mechanistic role in AAN has not been previously reported.

Methods

Male wild-type (WT), PD-1 KO and lymphocyte-deficient RAG-1 KO mice (all on C57Bl/6 background) were treated with AA 5 mg/kg by i.p. injection. Five and 14 days after initiating AA treatment renal function, injury and inflammation were assessed.

Results

Over time, a marked infiltration of CD45+ immune cells, especially T lymphocytes was observed in kidneys of WT mice after AA treatment (For example: CD4 T cells/g: Vehicle: 77,000 ± 11,000 vs. AA: 1,860,000 ± 250,000 at day 14). CD8 T cell, mononuclear phagocyte and PMN cell numbers were also elevated at day 14. Five days after AA treatment there were no differences in renal function between WT, PD-1 KO or RAG-1 KO mice as measured by creatinine or BUN levels. At day 14, RAG-1 KO mice had significantly higher BUN levels, while PD-1 KO mice had lower BUN levels compared to WT AA-treated mice (BUN in (mg/dl) in WT: 38 ± 7 vs. RAG-1 KO: 87 ± 11 vs. PD-1 KO: 16 ± 1). At day 14, RAG-1 KO kidneys exhibited higher innate leukocyte accumulation compared to WT mice. Conversely, PD-1 KO kidneys had lower innate leukocytes and dramatically reduced CD3+CD4+ T cell infiltration.

Conclusion

These results suggest that lymphocytes are protective in this intermediate-length exposure of mice to AA. Unexpectedly, PD-1 deficiency ameliorated renal dysfunction and inflammation, suggesting a pro-inflammatory role for this co-stimulatory molecule in AAN.

Funding

  • NIDDK Support