抗酶蛋白抑制因子(Azin1)抑制糖尿病肾病肾脏纤维化的机制研究

Nowadays, rapid growth of diabetes and diabetic nephropathy which lack of effective treatments exerts a great burden on society. Diabetic nephropathy is the leading cause of end stage renal disease. TGF-β signaling pathway plays an important role in the process of development of diabetic nephropathy. Azin1 can suppress TGF-β1/Smad3 signaling. A novel and potentially important preliminary finding was that Azin1 expression was reduced both in renal tubular epithelial cells during diabetic condition and in the kidney of patient and mouse with type 2 diabetic nephropathy. Furthermore, the reduction of Azin1 was related to the activation of TGF-β signaling and the upregulation of miR-433. Based on these findings, we hypothesize that Azin1 may play an essential role in the renal fibrosis of diabetic nephropathy. To test this hypothesis, we will firstly determine the effects of Azin1 in renal fibrosis under diabetic condition in vitro by gain or loss of function study. We will then examine the relationship of Azin1 between TGF-β signaling under diabetic condition in vitro. Next, we will validate the effects of overexpression of Azin1 on renal injury during diabetic nephropathy in type 2 diabetic mouse models. Finally, we will determine the correlation of Azin1/miR-433 levels in serum, urine and kidney with occurrence of diabetic nephropathy in human patients. This novel study is significant because an identification of the effects of Azin1 in diabetic nephropathy will throw light on the understanding the mechanism of diabetic nephropathy. MiR-433 is maybe a useful non-invasive diagnostic biomarker of diabetic nephropathy. Upregulation of Azin1 will provide us a novel therapeutic method to combat diabetic nephropathy.

目前，国内外糖尿病和糖尿病肾病患者激增，糖尿病肾病是导致终末期肾病的主要原因。TGF-β1/Smad3信号通路在糖尿病肾病发展过程中起到重要作用。Azin1可抑制TGF-β1/Smad3信号通路，我们首次发现在糖尿病肾病患者和动物模型肾脏内Azin1表达下调，并与TGF-β1/Smad3信号通路激活相关。我们通过功能获得及缺失方法，在肾脏细胞中上调或下调Azin1表达；探讨糖尿病条件下Azin1和TGF-β1/Smad3的信号通路相互作用的分子机制；并利用小鼠糖尿病肾病模型，应用超声微泡介导质粒转染技术，上调Azin1以治疗糖尿病肾病；并进一步研究临床不同阶段糖尿病肾病患者血、尿和肾组织Azin1/miR-433表达和疾病进展的关系，明确Azin1在糖尿病肾病肾脏纤维化中起到重要作用。为糖尿病肾病发病机制的探索提供新的理论基础，并为糖尿病肾病的早期诊断和有效治疗提供新思路。

目前，我国糖尿病患病率逐年升高，2010 年我国糖尿病患者约9240 万，其中2 型糖尿病占90%以上。糖尿病肾病是糖尿病最主要的微血管并发症之一,也是导致终末期肾病的主要原因。糖尿病和糖尿病肾病也已成为严重消耗医疗资源、阻碍国民经济发展的疾病。转化生长因子-β1/Smad3(TGF-β1/Smad3)信号通路通过促进肾脏纤维化形成，在糖尿病肾病纤维化过程中起到重要作用。抗酶蛋白抑制因子(Azin1)与TGF-β1/Smad3信号通路和纤维化关系密切。Azin1可抑制TGF-β1/Smad3信号通路，我们首次发现在糖尿病肾病患者和动物模型肾脏内Azin1表达下调，并与TGF-β1/Smad3信号通路激活相关。我们通过功能获得及缺失方法，在肾脏细胞中上调或下调Azin1表达；探讨糖尿病条件下（高糖和AGE刺激）Azin1和TGF-β1/Smad3的信号通路相互作用的分子机制；并利用小鼠糖尿病肾病（db/db小鼠）模型，应用超声微泡介导质粒转染技术，上调Azin1或下调miR-433以治疗糖尿病肾病；并进一步研究临床不同阶段糖尿病肾病患者血、尿和肾组织Azin1/miR-433表达和疾病进展的关系，明确Azin1/miR-433在糖尿病肾病肾脏纤维化中起到重要作用。Azin1、miR-433 和 hsa-miR-223-3p 或可作为糖尿病肾病病情诊断及治疗效果和预后判断的指标; Azin1 和 miR-433 或可作为糖尿病、糖尿病肾脏疾病及糖 尿病肾功能衰竭患者的新的潜在治疗靶点。为糖尿病肾病发病机制的探索提供新的理论基础，并为糖尿病肾病的早期诊断和有效治疗提供新思路。