Son Seung Seob, Jeong Hee Seul, Lee Seong-Woo, Lee Eun Soo, Lee Jeong Geon, Lee Ji-Hye, Yi Jawoon, Park Mi Ju, Choi Min Sun, Lee Donghyeong, Choi Sin Young, Ha Jiheon, Kang Jeong Suk, Cho Nam-Jun, Park Samel, Gil Hyo-Wook, Chung Choon Hee, Park Joon Seok, Kim Myung Hee, Park Jihwan, Lee Eun Young
Department of Medicine, Graduate School of Soonchunhyang University, Cheonan, Korea.
BK21 Four Project, College of Medicine, Soonchunhyang University, Cheonan, Korea.
Exp Mol Med. 2024 Dec;56(12):2673-2689. doi: 10.1038/s12276-024-01360-6. Epub 2024 Dec 2.
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 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.
肾纤维化会导致慢性肾脏病中出现不可逆的结构损伤，其特征为细胞外基质（ECM）异常积聚。尽管谷氨酰 - 脯氨酰 - tRNA合成酶1（EPRS1）是参与富含脯氨酸蛋白质合成的关键酶，但其在肾纤维化中的作用仍不清楚。本研究通过对纤维化肾脏的单细胞分析和免疫染色发现，患者和小鼠的纤维化肾脏中EPRS1表达水平升高，尤其是在成纤维细胞和近端肾小管上皮细胞中。此外，C57BL / 6 EPRS1杂合敲除（Eprs1）以及使用一流的EPRS1抑制剂DWN12088进行的药理学EPRS1抑制，通过防止成纤维细胞活化和近端肾小管损伤，对肾纤维化和功能障碍起到保护作用。有趣的是，体外实验表明，在转化生长因子β处理的条件下，EPRS1除了通过翻译途径外，还通过使成纤维细胞中的SMAD家族成员3以及受损近端小管中的信号转导和转录激活因子3磷酸化，介导非翻译途径。EPRS1敲低和催化抑制可抑制这些途径，防止成纤维细胞活化、增殖以及随后的胶原蛋白产生。此外，我们发现EPRS1会导致近端小管中的线粒体损伤，但这种损伤可通过EPRS1抑制而减轻。我们的研究结果表明，EPRS1介导的ECM积聚通过成纤维细胞活化和线粒体功能障碍诱导肾纤维化。因此，靶向EPRS1可能是减轻慢性肾脏病纤维化损伤的潜在治疗靶点。
