Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China.
Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, China.
J Cell Mol Med. 2024 May;28(9):e18336. doi: 10.1111/jcmm.18336.
Diabetic kidney disease (DKD), a primary microvascular complication arising from diabetes, may result in end-stage renal disease. Epigenetic regulation of endothelial mesenchymal transition (EndMT) has been recently reported to exert function in metabolic memory and DKD. Here, we investigated the mechanism which Sirt7 modulated EndMT in human glomerular endothelial cells (HGECs) in the occurrence of metabolic memory in DKD. Lower levels of SDC1 and Sirt7 were noted in the glomeruli of both DKD patients and diabetes-induced renal injury rats, as well as in human glomerular endothelial cells (HGECs) with high blood sugar. Endothelial-to-mesenchymal transition (EndMT) was sustained despite the normalization of glycaemic control. We also found that Sirt7 overexpression associated with glucose normalization promoted the SDC1 expression and reversed EndMT in HGECs. Furthermore, the sh-Sirt7-mediated EndMT could be reversed by SDC1 overexpression. The ChIP assay revealed enrichment of Sirt7 and H3K18ac in the SDC1 promoter region. Furthermore, hypermethylated in cancer 1 (HIC1) was found to be associated with Sirt7. Overexpression of HIC1 with normoglycaemia reversed high glucose-mediated EndMT in HGECs. The knockdown of HIC1-mediated EndMT was reversed by SDC1 upregulation. In addition, the enrichment of HIC1 and Sirt7 was observed in the same promoter region of SDC1. The overexpressed Sirt7 reversed EndMT and improved renal function in insulin-treated diabetic models. This study demonstrated that the hyperglycaemia-mediated interaction between Sirt7 and HIC1 exerts a role in the metabolic memory in DKD by inactivating SDC1 transcription and mediating EndMT despite glucose normalization in HGECs.
糖尿病肾病（DKD）是一种由糖尿病引起的主要微血管并发症，可能导致终末期肾病。最近有研究报道，内皮间充质转化（EndMT）的表观遗传调控在代谢记忆和 DKD 中发挥作用。在这里，我们研究了 Sirt7 在代谢记忆发生时调节人肾小球内皮细胞（HGEC）中 EndMT 的机制。DKD 患者和糖尿病诱导的肾损伤大鼠的肾小球以及高血糖的人肾小球内皮细胞（HGEC）中 SDC1 和 Sirt7 的水平均降低。尽管血糖控制正常，但内皮到间充质转化（EndMT）仍持续存在。我们还发现，与血糖正常化相关的 Sirt7 过表达促进了 SDC1 的表达并逆转了 HGEC 中的 EndMT。此外，SDC1 的过表达可以逆转 sh-Sirt7 介导的 EndMT。ChIP 检测显示 Sirt7 和 H3K18ac 在 SDC1 启动子区域富集。此外，还发现高甲基化癌症基因 1（HIC1）与 Sirt7 相关。在正常血糖条件下过表达 HIC1 可逆转 HGEC 中高葡萄糖介导的 EndMT。SDC1 的上调逆转了 HIC1 介导的 EndMT。此外，在 SDC1 的相同启动子区域观察到 HIC1 和 Sirt7 的富集。过表达的 Sirt7 逆转了 EndMT 并改善了胰岛素治疗的糖尿病模型中的肾功能。这项研究表明，高血糖介导的 Sirt7 和 HIC1 之间的相互作用通过抑制 SDC1 转录和介导 EndMT，在 HGEC 中即使血糖正常化也能发挥 DKD 代谢记忆的作用。
