肾小球系膜增生是糖尿病肾病(DN)的早期病理改变之一，但机制不清。我们前期发现高糖下lncRNA可作为竞争性内源RNA(ceRNA)，靶向调控miRNA及靶基因表达，参与DN发生(NO.81570747)。近期，我们通过RNA-seq、生物信息学技术构建DN相关ceRNA网络；进一步网络拓扑分析、qRT-PCR和荧光素酶检测证实lncRNA H2k2，miR449a，miR449b和Trim11在系膜细胞中形成核心网络；同时，EdU实验发现H2k2促进系膜细胞增殖。因此，我们提出：高糖下ceRNA核心网络lncRNA H2k2-miR449a/b-Trim11异常表达，激活Mek/Erk信号途径，启动下游增殖基因，刺激DN系膜增生。本项目拟在体内外明确该核心网络具体作用模式，以及通过Mek/Erk信号途径调控系膜增生，并探讨这一事件对DN进展的重要性和意义，为DN早期诊治提供新的突破点。

Glomerular mesangial cell proliferation plays an important role at the early stage of diabetic nephropathy (DN). However, the exact mechanism is not fully clear. In the previous study, we found lncRNA could act as a competing endogenous RNA (ceRNA) to regulate the expressions of the miRNA and the target gene in DN (NO.81570747). Recently, we found a DN related ceRNA network by RNA-seq and bioinformatics technique. Furthermore, the DN-related hub ceRNA network consisting of lncRNA H2k2, miR449a, miR449b and Trim11 was validated by topology analysis, qRT-PCR and luciferase assay. Moreover, we found lncRNA H2k2 could promote mesangial cell proliferation by EdU. Therefore, we hypothesize that under the high glucose condition, the DN-related hub ceRNA network-lncRNA H2k2-miR449a/b-Trim11 becomes abnormal, subsequently, the Trim11 related pathway Mek/Erk signal pathway is activated, causing the initiation of the expressions of the cell proliferation genes, resulting in mesangial cell proliferation of DN. This project intends to confirm the interaction of the hub network and the role of the hub network in mesangial cell proliferation in DN via Mek/Erk signal pathway in vivo and in vitro, which may provide a new insight into the prevention and treatment of DN.