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Abstract：
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.
摘要：
糖尿病肾病（DKD），糖尿病引起的原发性微血管并发症，可能导致终末期肾病。最近报道了内皮间质转化（EndMT）的表观遗传调节在代谢记忆和DKD中发挥功能。这里,我们研究了Sirt7调节人肾小球内皮细胞（HGECs）中EndMT在DKD代谢记忆发生中的机制。在DKD患者和糖尿病诱导的肾损伤大鼠的肾小球中发现SDC1和Sirt7水平较低，以及高血糖的人肾小球内皮细胞（HGECs）。尽管血糖控制正常化，内皮-间质转化（EndMT）仍持续。我们还发现与葡萄糖正常化相关的Sirt7过表达促进SDC1表达并逆转HGECs中的EndMT。此外，sh-Sirt7介导的EndMT可被SDC1过表达逆转。ChIP测定揭示了SDC1启动子区域中Sirt7和H3K18ac的富集。此外，发现癌症1中的高甲基化（HIC1）与Sirt7相关。正常血糖的HIC1过表达逆转了HGECs中高糖介导的EndMT。SDC1上调逆转了HIC1介导的EndMT的敲减。此外,在SDC1的同一启动子区域观察到HIC1和Sirt7的富集。在胰岛素治疗的糖尿病模型中，过度表达的Sirt7逆转了EndMT并改善了肾功能。这项研究表明，尽管HGECs中的葡萄糖正常化，但Sirt7和HIC1之间的高血糖介导的相互作用通过使SDC1转录失活并介导EndMT在DKD的代谢记忆中发挥作用。
