circ-Akap7调控MTDH介导肾小管上皮细胞衰老参与糖尿病肾病发生发展的机制研究

肾小管上皮细胞衰老是糖尿病肾病（DN）发生发展的主要原因之一，调控机制尚未完全明确。我们前期研究发现circRNA Akap7（circ-Akap7）在DN肾组织异常低表达。近期预实验显示circ-Akap7与肾小管上皮细胞衰老密切相关并通过衰老相关分泌表型活化肾间质成纤维细胞；通过RNA pull-down联合质谱筛选发现circ-Akap7与转移粘附基因(MTDH)相结合且低表达circ-Akap7上调MTDH表达。据此，我们提出假设：低表达circ-Akap7抑制与之结合的MTDH经泛素化降解进而上调MTDH表达促进肾小管上皮细胞衰老参与DN发生发展。本项目拟采用RNA免疫沉淀、Deletion-mapping、荧光原位杂交等技术从体内外系统并结合临床样品，深入探讨circ-Akap7调控MTDH介导肾小管上皮细胞衰老参与DN发生发展的分子机制，为临床DN防治提供新的分子靶点及思路。

Senescence of renal tubular epithelial cells plays an important role in the development of diabetic nephropathy(DN). However, the mechanism of tubular epithelial cells senescence is not clear. In our previous study, we found that circRNA Akap7(circ-Akap7)was significantly downregulated in diabetic renal tissues and loss of circ-Akap7 promoted tubular epithelial cells senescence. Application of RNA pull-down experiments to screen and found that circ-Akap7 bound with the DN-related protein Metadherin(MTDH). Therefore, we propose that circ-Akap7 interacts with MTDH and inhibits its functions. In the present study, we try to explore the association between circ-Akap7 and tubular epithelial cells senescence and renal injury in DN patients. And confirm that the circ-Akap7 directly combines with protein MTDH, and explore the importance of MTDH function silence in the senescence of renal tubular epithelial cells and renal injury in DN. Furthermore, we will use db/db mice, a well known of DN mice, to further explore the role of circ-Akap7 in the pathogensis of tubular epithelial cells senescence and renal injury in vivo. This research may help to discover a new effective target and theoretical basis for the prevention and treatment of DN.