IRF1/ZNF350/GPX4 介导的肾小管上皮细胞铁死亡促进慢性肾移植间质纤维化。
IRF1/ZNF350/GPX4-mediated ferroptosis of renal tubular epithelial cells promote chronic renal allograft interstitial fibrosis.
机构信息
Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Urology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
出版信息
Free Radic Biol Med. 2022 Nov 20;193(Pt 2):579-594. doi: 10.1016/j.freeradbiomed.2022.11.002. Epub 2022 Nov 7.
Renal interstitial fibrosis and tubular atrophy are essential pathological characteristics of chronic renal allograft dysfunction (CAD). Herein, we revealed that ferroptosis of renal tubular epithelial cells (RTECs) might contribute to renal tubular injury in CAD. Mechanistically, TNF-α induced ferroptosis by inhibiting GPX4 transcription through upregulating IRF1 in RTECs. IRF1 could bind with ZNF350 to form a transcription factor complex, which directly binds to the GPX4 promoter region to inhibit GPX4 transcription. Ferroptotic RTECs might secrete profibrotic factors, including PDGF-BB and IL-6, to activate neighboring fibroblasts to transform into myofibroblasts or induce EMT in adjacent RTECs. In conclusion, our results confirmed a novel role of ferroptosis in renal tubular injury and interstitial fibrosis, thereby providing insights into the pathogenesis of chronic renal allograft interstitial fibrosis during CAD.
肾间质纤维化和肾小管萎缩是慢性移植肾失功（CAD）的主要病理特征。在此，我们揭示了肾小管上皮细胞（RTEC）的铁死亡可能导致 CAD 中的肾小管损伤。在机制上，TNF-α 通过上调 RTEC 中的 IRF1 抑制 GPX4 转录从而诱导铁死亡。IRF1 可以与 ZNF350 形成转录因子复合物，该复合物直接与 GPX4 启动子区域结合以抑制 GPX4 转录。铁死亡的 RTEC 可能会分泌促纤维化因子，包括 PDGF-BB 和 IL-6，以激活邻近的成纤维细胞转化为肌成纤维细胞或诱导相邻 RTEC 发生 EMT。总之，我们的结果证实了铁死亡在肾小管损伤和间质纤维化中的新作用，从而为 CAD 期间慢性移植肾间质纤维化的发病机制提供了新的见解。
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