Xia Yuqi, Ye Zehua, Li Bojun, Yan Xinzhou, Yuan Tianhui, Li Lei, Song Baofeng, Yu Weimin, Rao Ting, Ning Jinzhuo, Zhu Jiefu, Li Xing, Mei Shuqin, Mao Zhiguo, Zhou Xiangjun, Cheng Fan
Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
Department of Nephrology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, China.
Commun Biol. 2025 Feb 22;8(1):286. doi: 10.1038/s42003-025-07735-3.
Long-term nephrocalcinosis leads to kidney injury, fibrosis, and even chronic kidney disease (CKD). Macrophage-to-myofibroblast transition (MMT) has been identified as a new mechanism in CKD, however, the effect of MMT in calcium oxalate (CaOx)-induced kidney fibrosis remains unclear. In this study, abundant MMT cells are identified by immunofluorescence (IF) and flow cytometry in kidney tissues of patients with CaOx-related CKD, a male mouse model, and CaOx-treated macrophages. Clodronate liposome (CLO)-mediated macrophage depletion attenuates fibrosis in male nephrocalcinosis mice. Transcriptomic sequencing reveals that histone methyltransferase (HMTs), EZH2, is highly expressed in nephrocalcinosis. Ezh2 inducible knock-out or inhibition by GSK-126 attenuates MMT and renal fibrosis. Mechanistically, ChIP and transcriptomic sequencing show that EZH2 inhibition reduces the enrichment of H3K27me3 on the Dusp23 gene promoter and elevates Dusp23 expression. The Co-IP and molecular docking analysis shows that DUSP23 mediates the dephosphorylation of pSMAD3 (Ser423/425). Thus, our study found that EZH2 promotes kidney fibrosis by meditating MMT via the DUSP23/SMAD3 pathway in nephrocalcinosis.
长期肾钙质沉着症会导致肾损伤、纤维化，甚至慢性肾脏病（CKD）。巨噬细胞向肌成纤维细胞转变（MMT）已被确定为CKD中的一种新机制，然而，MMT在草酸钙（CaOx）诱导的肾纤维化中的作用仍不清楚。在本研究中，通过免疫荧光（IF）和流式细胞术在CaOx相关CKD患者、雄性小鼠模型以及经CaOx处理的巨噬细胞的肾组织中鉴定出大量MMT细胞。氯膦酸盐脂质体（CLO）介导的巨噬细胞清除可减轻雄性肾钙质沉着症小鼠的纤维化。转录组测序显示，组蛋白甲基转移酶（HMTs）EZH2在肾钙质沉着症中高表达。Ezh2诱导敲除或用GSK - 126抑制可减轻MMT和肾纤维化。机制上，染色质免疫沉淀（ChIP）和转录组测序表明，EZH2抑制可降低H3K27me3在Dusp23基因启动子上的富集并提高Dusp23表达。免疫共沉淀（Co - IP）和分子对接分析表明，DUSP23介导pSMAD3（Ser423/425）的去磷酸化。因此，我们的研究发现，在肾钙质沉着症中，EZH2通过DUSP23/SMAD3途径介导MMT来促进肾纤维化。
