FUT8-CD147/VAT1调控肾小管上皮细胞线粒体功能促进DN肾间质纤维化进展的研究

肾脏线粒体功能障碍是糖尿病肾病（DN）进展的关键病理改变。囊泡胺转运蛋白-1（VAT1）负反馈调节线粒体融合，在肾脏病及组织纤维化中尚无研究报道。本项目前期研究发现抑制核心岩藻糖基转移酶FUT8表达可以改善DN小鼠肾脏细胞线粒体碎片化状态、抑制肾间质纤维化，并利用组学分析筛选出VAT1为FUT8调控的候选下游蛋白。VAT1自身并无核心岩藻糖基化（CF）修饰位点，研究报道，VAT1与CD147在特定条件下存在动态相互作用。糖基化跨膜蛋白CD147受CF修饰，作为分子伴侣与多种蛋白存在相互作用，并调节肾间质纤维化。本项目拟在前期创新性发现的基础上，利用肾小管FUT8条件性敲除小鼠，探讨FUT8调控CD147/VAT1相互作用介导线粒体功能障碍促进DN肾间质纤维化进展的机制。为开拓以糖基化修饰为靶点治疗/改善DN肾组织线粒体功能障碍及纤维化新途径奠定实验基础。

Mitochondrial dysfunction is the key pathological change in the progression of diabetic nephropathy (DN). Vesicle amine transport-1(VAT1) regulates mitochondrial fusion with negative feedback, and its role in renal disease and tissue fibrosis has not been reported. The preliminary study of this project found that inhibiting the expression of core fucosyltransferase FUT8 could improve the mitochondrial fragmentation state of kidney cells and inhibit renal interstitial fibrosis in DN mice, and VAT1 was selected as the candidate downstream protein regulated by FUT8 through omics analysis. VAT1 does not have core fucosylation (CF) modification sites, and it has been reported that VAT1 and CD147 interact dynamically under certain conditions. Glycosylated transmembrane protein CD147, modified by CF, interacts with a variety of proteins as a molecular chaperone and regulates renal interstitial fibrosis. On the basis of previous innovative findings, this project use renal tubular FUT8 conditional knockout mice intends to explore the mechanism of FUT8 regulating CD147/VAT1 interaction-mediated mitochondrial dysfunction to promote the progression of DN renal interstitial fibrosis. This study aims to lay the experimental foundation for developing a new way to treat or improve mitochondrial dysfunction and fibrosis of DN kidney by glycosylation modification as the target.