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Exp. Mol. Med., Dec 02 2024, | https://doi.org/10.1038/s12276-024-01360-6 EPRS1-mediated fibroblast activation and mitochondrial dysfunction promote kidney fibrosis

Seung Seob Son^1,2, Hee Seul Jeong^1,2, Seong-Woo Lee^1,2, Eun Soo Lee^3,4, Jeong Geon Lee⁵, Ji-Hye Lee^5,6, Jawoon Yi⁷, Mi Ju Park^1,2, Min Sun Choi^1,2, Donghyeong Lee^1,2, Sin Young Choi⁷, Jiheon Ha⁵, Jeong Suk Kang^8,9, Nam-Jun Cho^5,8, Samel Park^5,8, Hyo-Wook Gil^5,8, Choon Hee Chung^3,4, Joon Seok Park¹⁰, Myung Hee Kim¹¹, Jihwan Park⁷and Eun Young Lee^1,2,5,8,9

¹Department of Medicine, Graduate School of Soonchunhyang University, Cheonan, Korea.
²BK21 Four Project, College of Medicine, Soonchunhyang University, Cheonan, Korea.
³Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.
⁴Research Institute of Metabolism and Inflammation, Yonsei University Wonju College of Medicine, Wonju, Korea.
⁵Department of Medicine, College of Medicine, Soonchunhyang University, Cheonan, Korea.
⁶Department of Pathology, Soonchunhyang University Cheonan Hospital, Cheonan, Korea.
⁷School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea.
⁸Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea.
⁹Institute of Tissue Regeneration, College of Medicine, Soonchunhyang University, Cheonan, Korea.
¹⁰Drug Discovery Center, Daewoong Pharmaceutical Co. Ltd., Yongin, Korea.
¹¹Microbiome Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.

Corresponding author
Correspondence to Eun Young Lee.

Abstract

Kidney fibrosis causes irreversible structural damage in chronic kidney disease and is characterized by aberrant extracellular matrix (ECM) accumulation. Although glutamyl-prolyl-tRNA synthetase 1 (EPRS1) is a crucial enzyme involved in proline-rich protein synthesis, its role in kidney fibrosis remains unclear. The present study revealed that EPRS1 expression levels were increased in the fibrotic kidneys of patients and mice, especially in fibroblasts and proximal tubular epithelial cells, on the basis of single-cell analysis and immunostaining of fibrotic kidneys. Moreover, C57BL/6 EPRS1^tm1b heterozygous knockout (Eprs1^+/-) and pharmacological EPRS1 inhibition with the first-in-class EPRS1 inhibitor DWN12088 protected against kidney fibrosis and dysfunction by preventing fibroblast activation and proximal tubular injury. Interestingly, in vitro assays demonstrated that EPRS1-mediated nontranslational pathways in addition to translational pathways under transforming growth factor β-treated conditions by phosphorylating SMAD family member 3 in fibroblasts and signal transducers and activators of transcription 3 in injured proximal tubules. EPRS1 knockdown and catalytic inhibition suppressed these pathways, preventing fibroblast activation, proliferation, and subsequent collagen production. Additionally, we revealed that EPRS1 caused mitochondrial damage in proximal tubules but that this damage was attenuated by EPRS1 inhibition. Our findings suggest that the EPRS1-mediated ECM accumulation induces kidney fibrosis via fibroblast activation and mitochondrial dysfunction. Therefore, targeting EPRS1 could be a potential therapeutic target for alleviating fibrotic injury in chronic kidney disease.

논문정보

형식Research article
게재일2024년 12월 (BRIC 등록일 2024-12-04)
연구진국내 연구진
분야 의약학 > 응용의학

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