Page 33 - 南京医科大学自然版

第45卷第5期 南京医科大学学报（自然科学版）
2025年5月 Journal of Nanjing Medical University（Natural Sciences） ·619 ·

·基础研究·

艾拉莫德抑制巨噬细胞向肌成纤维细胞转分化减缓慢性移植

肾间质纤维化

杨铖铖 ，倪 斌 ，郑 明 ，谭若芸 ，顾 民 ，沈百欣 1*
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南京医科大学第二附属医院泌尿外科，江苏 南京 210011；南京医科大学第一附属医院泌尿外科，江苏 南京 210029
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［摘 要］ 目的：探讨艾拉莫德（iguratimod，IGT）在慢性移植肾间质纤维化中的作用和机制。方法：构建并鉴定了同种异体小
鼠慢性移植肾失功（chronic renal allograft dysfunction，CAD）模型，并使用IGT灌胃干预，通过组织学染色评估移植肾损伤及纤
维化程度，通过免疫荧光染色、Western blot及qRT⁃PCR等方法检测IGT干预后的CAD小鼠移植肾中纤维化指标和巨噬细胞向
肌成纤维细胞转分化（macrophage⁃to⁃myofibrolast transition，MMT）的变化。使用转化生长因子（transforming growth factor，TGF）⁃β
诱导小鼠原代骨髓来源巨噬细胞（bone marrow⁃derived macrophage，BMDM）发生 MMT 并使用 IGT 干预，转录组测序用于探索
IGT调节MMT的下游分子机制。结果：同种异体小鼠CAD模型出现了显著的移植肾间质纤维化，免疫荧光染色显示MMT相
关标志物在移植肾中显著上调，IGT可显著减轻16周时CAD小鼠的移植肾间质纤维化，并减少MMT细胞的数量。体外实验表
明IGT 可显著减缓TGF⁃β诱导的MMT，细胞转录组测序结果表明IGT 可能通过诱导铁死亡相关通路抑制MMT、减轻纤维化。
结论：IGT可能通过诱导铁死亡相关通路抑制MMT并减轻移植肾间质纤维化。这可能为IGT在同种异体肾移植中的应用提供
新见解。
［关键词］ 艾拉莫德；慢性移植肾失功；巨噬细胞向肌成纤维细胞转分化；间质纤维化；铁死亡
［中图分类号］ R699.2 ［文献标志码］ A ［文章编号］ 1007⁃4368（2025）05⁃619⁃08
doi：10.7655/NYDXBNSN240810

Iguratimod alleviates interstitial fibrosis in chronic allograft dysfunction by inhibiting
macrophage⁃to⁃myofibroblast transition

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YANG Chengcheng ，NI Bin ，ZHENG Ming ，TAN Ruoyun ，GU Min ，SHEN Baixin
Department of Urology，the Second Affiliated Hospital of Nanjing Medical University，Nanjing 210011；Department
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of Urology，the First Affiliated Hospital of Nanjing Medical University，Nanjing 210029，China

［Abstract］ Objective：To investigate the role and mechanism of iguratimod（IGT）in interstitial fibrosis of chronic renal allograft
dysfunction（CAD）in transplanted kidneys. Methods：A mouse CAD model was constructed and validated. IGT was administered via
gavage. Histological staining was used to assess injury and fibrosis in transplanted kidneys. Immunofluorescence staining，Western
blot，and qRT ⁃ PCR were utilized to detect fibrosis markers and changes in macrophage ⁃ to ⁃ myofibroblast transition（MMT）in
transplanted kidneys of the CAD mice. Transforming growth factor（TGF）⁃β was used to induce MMT in primary mouse bone marrow⁃
derived macrophages（BMDM）in vitro，followed by IGT intervention. Transcriptome sequencing was employed to explore the
downstream molecular mechanisms by which IGT regulated MMT. Results：The CAD groups developed severe interstitial fibrosis in
the transplanted kidneys. Immunofluorescence staining revealed that markers related with MMT were significantly upregulated in the
transplanted kidneys. Treatment with IGT markedly reduced interstitial fibrosis in the transplanted kidneys of the CAD mice at 16
weeks，along with a decrease in MMT cell numbers. In vitro experiments demonstrated that IGT significantly inhibited TGF⁃β⁃induced
MMT，and cell transcriptome sequencing results suggest that IGT may mitigate MMT and reduced fibrosis by activating ferroptosis⁃
related pathways. Conclusion：IGT may alleviate interstitial fibrosis in transplanted kidneys and slow the progression of CAD by
upregulating the ferroptosis⁃related pathway to inhibit MMT. This may provide new insights for the future application of IGT in allograft
kidney transplantation.
［Key words］ iguratimod；chronic renal allograft dysfunction；macrophage⁃to⁃myofibroblast transition；interstitial fibrosis；ferroptosis
［基金项目］ 国家自然科学基金（82270817） ［J Nanjing Med Univ，2025，45（05）：619⁃626］
通信作者（Corresponding author），E⁃mail：baixinshen@njmu.edu.cn（ORCID：0000⁃0002⁃9651⁃7762）
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