环状RNA-010383在糖尿病肾病中发生的作用及其分子机制研究

Diabetic nephropathy (DN) is one of the most microvascular complications of diabetes. However, the mechanism is not completely clear. In our previous study, we applicated the circRNAs microarray technology to detect and screen the specific circRNAs of diabetic renal tissues, and validated them using quantitative real-time polymerase chain reaction. Results showed that circRNA-010383 was significantly downregulated in renal tissues of db/db mice, and was tightly associated with mesangial cell proliferation. Further bioinformatic experiments found that circRNA-010383 contains several target sites of DN-related miR-135a. Therefore, we speculate that circRNA-010383 interacts with miR-135a, and plays an important role in the development of DN. In the present study, we aim to further confirm that the interaction between circRNA-010383 and miR-135a through immunoprecipitation, biotin-coupled miRNA pull down and luciferase assay. This research may help to discover the new mechanism of DN, and represent potential targets for drug interventions to improve DN.

糖尿病肾病（DN）是糖尿病常见且难治的血管并发症，发病机制尚未完全明确。我们前期研究应用circRNAs芯片技术检测并筛选糖尿病肾病特异表达的circRNAs，发现circRNA-010383在糖尿病肾病肾组织异常低表达，且与系膜细胞增殖密切相关。经生物信息学预测，发现circRNA-010383可能调控糖尿病肾病相关miR-135a, 发挥海绵作用。基于此，我们提出了进一步研究circRNA-010383在糖尿病肾病发生中的作用及分子机制。本项目拟进一步采用免疫印迹、生物素化miRNA pull down及双荧光酶报告系统等手段证实circRNA-010383与miR-135a相互作用，并探讨这一事件对系膜细胞增殖及细胞外基质的影响。本研究有望揭示糖尿病肾病发生的新机制，为糖尿病肾病的治疗确立新的靶点提供更充分的科学依据。

糖尿病肾病（DN）是糖尿病常见的难治微血管并发症，致死率高。近年环状RNA (circRNA)在动脉粥样硬化、神经系统紊乱、糖尿病和肿瘤等疾病发生过程中起着重要的作用，而在DN发病中尚未被报道。我们主要研究发现：1）高糖下调circRNA-010383在系膜细胞中的表达，与miR-135a、TPRC1表达有相关性；2）circRNA-010383是miR-135a的Sponge；3）下调系膜细胞circRNA-010383，系膜细胞基质合成显著增加并下调TRPC1表达； 4）上调circRNA-010383可逆转高糖诱导的系膜细胞基质合成，且回复TRPC1表达；5）上调miR-135a的表达可抵消circRNA-010383过表达的作用；6）体内上调circRNA-010383可减轻糖尿病肾脏损伤；7）体内上调circRNA-010383延缓糖尿病肾病肾脏纤维化。