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Kidney Int., Feb 04 2024, S0085-2538(24)00067-X | https://doi.org/10.1016/j.kint.2024.01.011 Glutamyl-prolyl-tRNA synthetase (EPRS1) drives tubulointerstitial nephritis-induced fibrosis by enhancing T cell proliferation and activity

Chaelin Kang ^1∗, Donghwan Yun ^1,2∗, Haein Yoon ¹, Minki Hong ¹, Juhyeon Hwang¹, Hyun Mu Shin ¹, Seokwoo Park ², Seongmin Cheon ³, Dohyun Han ^3,4, Kyung Chul Moon ⁵, Hye Young Kim ¹, Eun Young Choi ¹, Eun-Young Lee ⁶, Myung Hee Kim ⁶, Chang Wook Jeong ⁷, Cheol Kwak ⁷, Dong Ki Kim ², Kook-Hwan Oh ², Kwon Wook Joo ², Dong-Sup Lee¹, Yon Su Kim ^1,2, Seung Seok Han ²

¹Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea

²Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea

³Proteomics Core Facility, Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea

⁴Transdisciplinary Department of Medicine and Advanced Technology, Seoul National University Hospital, Seoul, Korea

⁵Department of Pathology, Seoul National University College of Medicine, Seoul, Korea

⁶Microbiome Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea

⁷Department of Urology, Seoul National University College of Medicine, Seoul, Korea

^∗Co-first authors

Correspondence: Seung Seok Han, MD, PhD

Abstract

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 house keeping 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 EPRS1 ^high 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, were 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.

논문정보

형식Research article
게재일2024년 02월 (BRIC 등록일 2024-02-14)
연구진국내 연구진
분야 의약학 > 면역의학

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