[국문]
*논문명: 만성콩팥병의 신규 치료제로 EPRS1 억제제의 가능성
*내용: Glutamyl-prolyl-tRNA synthetase 1 (EPRS1)는 콜라겐 섬유와 같이 프롤린을 다량 함유하는 단백질의 합성에 중요한 역할을 하는 효소로 알려져 있다. 만성콩팥병 동물 모델에서 EPRS1의 발현이 증가된 것을 확인하였다. 이 증가는 콩팥의 섬유모세포와 근위세뇨관 세포에서 증가된 것을 단일 세포 전사체 분석, 웨스턴 블롯, RT-PCR, 면역염색법을 이용하여 분자 수준의 기전을 확인할 수 있었다. 한편, EPRS1 억제제를 사용하여 만성콩팥병의 주요증상인 섬유화증을 크게 개선하였고, 콩팥기능의 수치를 완화시킴으로 치료 효과를 확인하였다.
[영문]
*Title: EPRS1-mediated fibroblast activation and mitochondrial dysfunction promote kidney fibrosis
*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 EPRS1tm1b 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.
