肾小管上皮细胞来源外泌体circRNA-HOXB3诱导糖尿病肾病足细胞焦亡的机制研究

糖尿病肾病（DN）已是终末期肾脏病的首要病因，但其发生机制未明。我们前期研究发现： circRNA-HOXB3在高糖刺激肾小管上皮细胞外泌体表达增多；生物信息学预测circRNA-HOXB3与miR-29b-2-5p存在结合位点，GSK3β是miR-29b-2-5p的靶基因。已证实GSK3β参与了DN的发生发展；肾小管上皮细胞外泌体可转运至足细胞。因此假设：糖尿病肾病时，肾小管上皮细胞来源外泌体circRNA-HOXB3表达水平升高，其作为miR-29b-2-5p的ceRNA调控GSK3β，激活NF-κB/NLRP3通路，诱导糖尿病肾病足细胞焦亡。本课题拟采用外泌体示踪、电镜、免疫荧光双染、激光共聚焦及分子生物学技术手段，从分子、细胞、组织以及动物整体水平等多层面揭示外泌体circRNA-HOXB3诱导足细胞焦亡的机制。为寻找DN早期无创诊断标志物奠定理论依据，也为临床治疗DN开拓新思路。

Diabetic nephropathy（DN）is the leading cause of end-stage kidney disease, but its potential pathogenesis is still unclear. Our previous studies revealed high glucose stimulates expression of circRNA-HOXB3 in renal tubular epithelial cells-derived exosomes. There is a binding site of circRNA-HOXB3 in miR-29b-2-5p. GSK3β is a target gene of miR-29b-2-5p and has been proved to involve in the development of DN.Tubular epithelial cells-derived exosomes can reach podocytes. Therefore, we hypothesized that the expression level of circRNA-HOXB3 is increased in renal tubular epithelial cells-derived exosomes which can regulate GSK3β as ceRNA of miR-29b-2-5p in diabetic nephropathy. Furthermore podocytes pyroptosis are induced by activating NF-κB/NLRP3 signaling pathway in diabetic nephropathy. The results will be assessed with different methods including exosome-tracing technique,electron microscopy, confocal microscopy and molecular biology techniques. The present project aimes to, from the levels of molecular, cellular,tissue, and animal, unveil the mechanism of exosomal circRNA-HOXB3 induced podocyte pyroptosis. This project would like to provide theoretical basis to finding a new diagnostic markers,and provide new ideas for clinical treatment of DN.