Glutamyl-prolyl-tRNA synthetase (EPRS1) drives tubulointerstitial nephritis-induced fibrosis by enhancing T cell proliferation and activity

Kidney Int. 2024 May;105(5):997-1019. doi: 10.1016/j.kint.2024.01.011. Epub 2024 Feb 5.


Toxin- and drug-induced tubulointerstitial nephritis (TIN), characterized by interstitial infiltration of immune cells, frequently necessitates dialysis for patients due to irreversible fibrosis. However, agents modulating interstitial immune cells are lacking. Here, we addressed whether the housekeeping enzyme glutamyl-prolyl-transfer RNA synthetase 1 (EPRS1), responsible for attaching glutamic acid and proline to transfer RNA, modulates immune cell activity during TIN and whether its pharmacological inhibition abrogates fibrotic transformation. The immunological feature following TIN induction by means of an adenine-mixed diet was infiltration of EPRS1high T cells, particularly proliferating T and γδ T cells. The proliferation capacity of both CD4+ and CD8+ T cells, along with interleukin-17 production of γδ T cells, was higher in the kidneys of TIN-induced Eprs1+/+ mice than in the kidneys of TIN-induced Eprs1+/- mice. This discrepancy contributed to the fibrotic amelioration observed in kidneys of Eprs1+/- mice. TIN-induced fibrosis was also reduced in Rag1-/- mice adoptively transferred with Eprs1+/- T cells compared to the Rag1-/- mice transferred with Eprs1+/+ T cells. The use of an EPRS1-targeting small molecule inhibitor (bersiporocin) under clinical trials to evaluate its therapeutic potential against idiopathic pulmonary fibrosis alleviated immunofibrotic aggravation in TIN. EPRS1 expression was also observed in human kidney tissues and blood-derived T cells, and high expression was associated with worse patient outcomes. Thus, EPRS1 may emerge as a therapeutic target in toxin- and drug-induced TIN, modulating the proliferation and activity of infiltrated T cells.

Keywords: EPRS1; fibrosis; kidney; tubulointerstitial nephritis; γδ T cell.

MeSH terms

  • Amino Acyl-tRNA Synthetases* / metabolism
  • Animals
  • CD8-Positive T-Lymphocytes
  • Cell Proliferation
  • Fibrosis
  • Homeodomain Proteins
  • Humans
  • Mice
  • Nephritis, Interstitial* / chemically induced
  • Nephritis, Interstitial* / drug therapy
  • Nephritis, Interstitial* / genetics
  • Renal Insufficiency*


  • Amino Acyl-tRNA Synthetases
  • glutamyl-prolyl-tRNA synthetase
  • Homeodomain Proteins