组蛋白去甲基化酶UTX对糖尿病肾病的调控作用研究

Chronic hyperglycemia can cause multiple organ dysfunction and failure in diabetic patients, which leads to the development of diabetic complications. Diabetic nephropathy (DN) is one of the major microvascular diabetic complications, and is the major cause of end stage renal failure. Therefore, understanding the exact mechanisms of the pathogenesis of DN is of great importance for the prevention and intervention of DN. UTX, a histone demethyltransferase for H3K27me2/3, is known to regulate embryonic development and proliferation of T cells, etc. We have recently found that the expression levels of UTX were significantly increased in the kidneys of diabetic mice and lipid stimulated renal cell lines, while manipulating UTX level affects the lipid-induced transcription of inflammatory cytokines in cultured renal cells. Furthermore, using a UTX inhibitor not only regulates H3K27me2/3 levels in vitro and in vivo, but also inhibits the transcription of inflammatory cytokines in cultured cells. Based on these pilot studies, we determined to use renal cell lines, primary glomerular mesangial/epithelial cells and kidney specific Utx knockout or transgenic mice to elucidate how UTX affects the development of DN through histone modifications on regulation of TGF-beta 1 and inflammation. Moreover, we plan to treat diabetic mice with a UTX inhibitor to explore the potential of inhibiting UTX as a target for DN treatment. This project shall shed light on the molecular mechanisms of the pathogenesis of DN, and may even provide novel therapeutics for DN.

长期高血糖可引起糖尿病患者多种器官功能障碍和衰竭，导致并发症。糖尿病肾病（DN）为糖尿病主要微血管并发症，是终末期肾脏疾病的首要成因，研究DN发病机制及其治疗药物对于防治DN意义重大。组蛋白去甲基化酶UTX具有调节胚胎发育和T细胞增殖等生物功能。申请人前期发现UTX在糖尿病鼠肾脏及高脂刺激的肾细胞系中均表达显著上升，肾细胞中过表达或敲低UTX可调控高脂引发的炎症因子转录；而UTX抑制剂可在体内外调控H3K27me2/3水平，并在细胞水平上调控炎症因子的转录。据此，申请人计划在细胞和动物水平，利用肾细胞系、原代肾系膜/上皮细胞及肾脏特异性UTX敲除/转基因小鼠，深入研究UTX如何通过组蛋白修饰来调控TGF-beta1和炎症通路，从而影响DN；并探索以UTX为靶点治疗DN的前景。本项目有望进一步阐明DN发病机制并为其治疗提供理论依据。

糖尿病肾病(DN)是一种常见糖尿病微血管并发症，以肾小球硬化和肾病综合征为特征，是糖尿病病人最重要的并发症之一。由于DN存在复杂的代谢紊乱，一旦发展到终末期肾脏病，治疗上往往比其它肾脏疾病更加棘手，因此及时防治对于延缓糖尿病肾病意义重大。UTX是组蛋白H3K27me2/3的去甲基化酶，本项目研究发现：UTX在糖尿病小鼠和糖尿病患者肾脏中表达量均显著性上升；在小鼠肾小球系膜细胞中，UTX通过影响H3K27me3在炎症因子启动子区域的募集，从而调控炎症因子的转录水平；发现UTX还通过与p53蛋白结合，从而影响肾脏细胞内DNA损伤反应。课题进一步研究了以UTX为靶点在糖尿病肾病治疗中的作用，对糖尿病小鼠进行腹腔注射UTX的抑制剂GSK J4，显示GSK J4能改善糖尿病引起的肾功能紊乱，抑制糖尿病引起的肾脏炎症、纤维化和DNA损伤。在此基础上，本研究构建了肾脏特异性敲除Utx小鼠，结果揭示了肾脏特异性敲除Utx能有效抑制高脂食物喂养引起的肾脏炎症和脂质过度积累。本研究为进一步探索糖尿病肾病的发病机制提供了新的理论基础，为糖尿病肾病的临床防治提供了潜在靶点和治疗方向。总之，本项目圆满完成并取得了一系列原创性成果。