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Abstract: FR-PO162

Inhibition of EPRS Reduces Tubulointerstitial Nephritis-Induced Fibrosis via Suppression of T Cell Proliferation and γδ T Cell Activation

Session Information

  • AKI: Mechanisms - II
    November 04, 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

  • Han, Seung Seok, Seoul National University Hospital, Jongno-gu, Korea (the Republic of)
  • Yun, Donghwan, Seoul National University Hospital, Jongno-gu, Korea (the Republic of)
  • Kim, Dong Ki, Seoul National University Hospital, Jongno-gu, Korea (the Republic of)
  • Oh, Kook-Hwan, Seoul National University Hospital, Jongno-gu, Korea (the Republic of)
  • Joo, Kwon Wook, Seoul National University Hospital, Jongno-gu, Korea (the Republic of)
  • Kim, Yon Su, Seoul National University Hospital, Jongno-gu, Korea (the Republic of)
Background

Acute tubulointerstitial nephritis (ATIN), characterized by interstitial infiltration of immune cells, ultimately makes patients undergo dialysis because of irreversible fibrosis, but the agents modulating interstitial immune cells are lacking. The present study addressed whether glutamyl-prolyl-transfer RNA synthetase (EPRS), attaching glutamine and proline to transfer RNA, modulates the immune cell activity on ATIN and its pharmacological inhibition abrogates fibrotic transformation.

Methods

Wild-type (WT) and hetero-knockout (Eprs+/–) mice were treated with adenine-mixed diet to induce ATIN, and their immune and fibrotic profiles were compared. Small molecule inhibitor against EPRS was used in both in vivo and in vitro models to validate its therapeutic prospect. Human ATIN samples were used to translate the mouse results.

Results

The EPRS expression in certain immune cell subsets strongly increased after the ATIN induction, such as proliferating T cells and γδ T cells. The proliferation capacity of both CD4+ and CD8+ T cells and the interleukin-17 production of γδ T cells decreased in ATIN-induced Eprs+/– kidneys compared with in the counterpart WT kidneys. This different immunological milieu in Eprs+/– kidneys lowered fibrotic transformation compared to in WT kidneys at the chronic phase of ATIN (Figure 1). The use of inhibitor against EPRS protected the above immunopathological process on ATIN. The inhibitor also reduced proliferation of human blood-derived T cells and activity of γδ T cells similarly to the mouse results. The high expression of EPRS in human kidneys with biopsy-proven ATIN correlated with overzealous tubulointerstitial fibrosis.

Conclusion

The increased expression of EPRS in infiltrated proliferating T cells and γδ T cells is immunofibrotic driver of ATIN. Pharmacological inhibition of EPRS attenuates both inflammation and subsequent fibrosis on ATIN via suppression of T cell proliferation and γδ T cell activation, which will be a potential option for treatment of ATIN.

Kidney damage markers in WT and Eprs+/- mice. AD, adenin-mixed diet; ND, normal diet.

Funding

  • Commercial Support