脂联素特异性调节的miRNA在糖尿病肾病中的作用及机制研究

Diabetic nephropathy (DN) is the most common complication of diabetes , which is a common cause of chronic renal failure ,but the pathogenesis is unclear. As a new regulatory mechanism, miRNA involved in a wide range of development and progression of DN , miRNA actived and formed a series of complex regulatory networks in DN. The study of the relationship between miRNA and DN will provide new targets for understanding the pathogenesis and treatment of DN. Adiponectin (APN) has acted as a major adipokines of the anti-inflammatory and improving insulin resistance, which can modulate the expression of miRNA in the role of anti-inflammation. At the same time , clinical studies have shown the close relationship between the plasma APN and DN.But whether adiponectin by specific regulation of microRNA to achieve the protective effect of DN has not been reported . This study intends to use miRNA-seq technology to filter out different miRNAs of DN in mouse kidney, later to find the specific miRNA regulated by overexpressing APN, and to analyze their role in DN. Adiponectin specific microRNA regulation is likely to provide a richer target for the treatment of DN, and add more anti-DN drug family members .

糖尿病肾病（DN）是糖尿病最常见的并发症之一，是慢性肾衰的常见病因，其发病机制尚不清楚。miRNA作为一种全新的调控机制广泛的参与了DN发生和发展，DN时肾脏内一系列的miRNA激活并形成复杂的调控网络，研究miRNA与DN的关系，将为理解DN发病及治疗提供新的靶点。脂联素（APN）是目前发现的具有抗炎、改善胰岛素抵抗的重要脂肪细胞因子，其可以通过调节miRNA的表达而发挥抗炎的作用，同时临床研究表明血浆APN浓度与DN关系密切。但脂联素是否通过特异性调节microRNA来实现对DN的保护作用目前尚未见报道。本研究拟用miRNA-seq技术筛选出DN小鼠肾脏差异表达的miRNAs后，在DN小鼠肾脏过表达APN来寻找其特异调节的miRNA，并分析它们在DN中的作用机制。研究脂联素特异性调节的microRNA极有可能为治疗DN提供更加丰富的靶点，并为抗DN药物家族添加更多新药成员。

糖尿病肾病（DN）是糖尿病最常见的并发症之一，是慢性肾衰的常见病因，其发病机制尚不清楚。miRNA作为一种全新的调控机制广泛的参与了DN发生和发展。本项目通过体内、外研究发现发现糖尿病肾病时miR-21、miR-196a的表达水平显著上调，脂联素表达水平降低，而肾脏过表达脂联素后，DN小鼠肾脏中miR-196a、miR-21的表达水平降低。脂联素作用于DN细胞后，miR-21和miR-196a的表达降低，而其靶基因PTEN表达水平升高明显，PTEN下游基因PI3K p85α、P-AKT(Ser473)、P-Smad3和Col4a1表达水平降低。收集维吾尔族糖尿病（DM）与糖尿病肾病患者血清，利用ELISA检测血清脂联素后发现，与正常组相比，DM组和DN组患者血清脂联素水平降低且差异有统计学意义,进一步分析血清脂联素水平与miRNA表达的相关性发现，血清miR-21和miR-196a表达与脂联素水平呈负相关。本研究结果提示脂联素可能通过降低miR-21和miR-196a、升高PTEN表达水平后，抑制PI3K/AKT信号通路的激活，减轻肾脏纤维化程度，具体作用机制有待于进一步的研究。