miR-27a调节Prohibitin表达对糖尿病肾小管上皮细胞氧化损伤的作用机制

Mounting evidence has implicated miRNAs in the development of diabetic nephropathy (DN). MicroRNAs (miRNAs) are endogenously expressed, small noncoding RNAs that negatively regulate gene expression by binding to the 3′-untranslated region (3′-UTR) of target mRNAs. miR-27a which is in abundance in kidneys can regulate Prohibitin level by binding the 3′untranslated region. Previous studies from our group demonstrated that miR-27a play important roles in the mesangial cell proliferation. However, to date little is known regarding miR-27a in DN. Preliminary experiments from our group have proved the increase of miR-27a level in human renal tubular epithelial cell under high glucose conditions, which was accompanied with significant decrease of Prohibitin expression, and reduction of the mitochondrial membrane potential. But its mechanism remains to be further discussed. Thus, we hypothesize that miR-27a participates in renal tubular epithelial cell oxidative injury through regulating the expression of Prohibitin in DN. Therefore, in this present study, by utilizing the techniques of molecular biology and diabetic mice, we are intended to study the role of miR-27a on Prohibitin expression in human renal tubular epithelial cell, and investigate the role and molecular mechanism of miR-27a on the oxidant stress response through the perspective of cells and animals. This subject provides a theoretical basis for deeply understanding the relationship of miR-27a and DN and revealing the therapeutic strategies for combating DN.

microRNAs与糖尿病肾病（DN）发生发展密切相关，可通过与其靶基因 3′端非转录区域结合发挥生物学效应。miR-27a主要存在于肾脏，我们前期研究发现miR-27a在DN系膜细胞增殖中起重要作用，但迄今对miR-27a与DN的关系仍知之甚少。我们预实验结果提示在高糖培养的人肾小管上皮细胞（HK-2）中miR-27a表达升高，伴随Prohibitin表达降低，线粒体膜电位下降，但其机制尚不清楚。据此我们提出假说：miR-27a可能通过靶向调节Prohibitin表达参与糖尿病肾小管上皮细胞氧化损伤。为此，本课题将在细胞和动物水平上，借助于各种分子生物学和糖尿病小鼠的技术手段，明确miR-27a对HK-2细胞中Prohibitin表达的影响，探讨miR-27a对糖尿病肾小管上皮细胞氧化损伤的调控机制。本研究将从miR-27a这个新视点探讨DN的发生机制，为寻找DN新的治疗靶点提供新思路。

microRNAs与糖尿病肾病（DN）发生发展密切相关，可通过与其靶基因3′端非转录区域结合发挥生物学效应。miR-27a主要存在于肾脏，我们前期研究发现miR-27a在DN系膜细胞增殖中起重要作用，但迄今对miR-27a与DN的关系仍知之甚少。我们预实验结果提示在高糖培养的人肾小管上皮细胞（HK-2）中miR-27a表达升高，伴随Prohibitin表达降低，线粒体膜电位下降，但其机制尚不清楚。本课题在细胞和动物水平上，借助于各种分子生物学和糖尿病小鼠的技术手段，明确miR-27a对HK-2细胞中Prohibitin表达的影响，探讨miR-27a对糖尿病肾小管上皮细胞氧化损伤的调控机制。本项目发现：（1）抑制miR-27a可以改善db/db小鼠的肾功能及肾脏纤维化。（2）抑制miR-27a可改善db/db小鼠肾脏线粒体功能障碍。（3）miR-27a可直接与Prohibitin 3′‐UTR结合并下调其表达。（4）miR-27a/prohibitin调控高糖诱导的HK-2细胞线粒体功能障碍。本研究从miR-27a这个新视点探讨DN的发生机制，为寻找DN新的治疗靶点提供新思路。