Yang Donglin, Yin Rongjiang, Zhang Xiaomin, Wang Xiaohui, Pei Xiaobin, Guo Zijie, Qiao Pengyue, Zhu Kehan, Wang Lin, Du Pengchao
College of Basic Medical, Binzhou Medical University, Yantai, Shandong, P.R. China.
Department of Thoracic Surgery, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong, P.R. China.
PLoS One. 2025 Jun 17;20(6):e0326217. doi: 10.1371/journal.pone.0326217. eCollection 2025.
Diabetic nephropathy (DN) is one of the most serious microvascular complications of diabetes mellitus. It is characterized by progressive tubulointerstitial fibrosis. The aim of this study was to investigate the role of exosomal circular RNA (circRNAs) in regulating fibroblast growth factor 9 (FGF9) expression in DN through a competitive endogenous RNA (ceRNA) mechanism, and to reveal its potential therapeutic targets. Exosomes were isolated from serum of 3 healthy people and 3 patients with DN by ultra-fast centrifugation method, and the circRNA-miRNA-FGF9 regulatory network was constructed by combining high-throughput circRNA sequencing, bioinformatics analysis and weighted co-expression network (WGCNA). The results showed that the expression of circRNAs in serum exosomes of DN patients was significantly down-regulated, and hsa_circ_0006382 and hsa_circ_0019539 targeted the expression of FGF9 by binding to miR-34a-5p, miR-766-3p, miR-147a and miR-27a-3p. Further verification showed that the expression of FGF9 was decreased in renal tissues of DN patients (AUC = 0.902), and its recombinant protein could inhibit the expression of α-SMA and vimentin in high glucose-induced NRK-52E cells, indicating that activation of the circRNA/miRNA-FGF9 network promotes the EMT of renal tubular epithelial cells. This study revealed for the first time the mechanism of the circRNA-miRNA-FGF9 regulatory network in DN fibrosis, providing a theoretical basis for the development of diagnostic markers and targeted therapy strategies based on exosomal circRNA.
糖尿病肾病（DN）是糖尿病最严重的微血管并发症之一。其特征为进行性肾小管间质纤维化。本研究旨在探讨外泌体环状RNA（circRNAs）通过竞争性内源RNA（ceRNA）机制调控DN中成纤维细胞生长因子9（FGF9）表达的作用，并揭示其潜在治疗靶点。采用超速离心法从3名健康人和3名DN患者的血清中分离外泌体，并结合高通量circRNA测序、生物信息学分析和加权共表达网络（WGCNA）构建circRNA-miRNA-FGF9调控网络。结果显示，DN患者血清外泌体中circRNAs的表达显著下调，且hsa_circ_0006382和hsa_circ_0019539通过与miR-34a-5p、miR-766-3p、miR-147a和miR-27a-3p结合靶向FGF9的表达。进一步验证表明，DN患者肾组织中FGF9表达降低（AUC = 0.902），其重组蛋白可抑制高糖诱导的NRK-52E细胞中α-SMA和波形蛋白的表达，表明circRNA/miRNA-FGF9网络的激活促进肾小管上皮细胞的上皮-间质转化（EMT）。本研究首次揭示了circRNA-miRNA-FGF9调控网络在DN纤维化中的机制，为基于外泌体circRNA开发诊断标志物和靶向治疗策略提供了理论依据。
