内皮细胞分泌含miR-221微囊泡介导系膜细胞损伤的机制研究

Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes mellitus, which is characterized by extracellular matrix (ECM) accumulation in glomeruli. However, the mechanism of hyperglycemia induced ECM remolding has not been fully elucidated. It has been proved that mesangial cell injury contributed to ECM expansion and Ets-1/MMPs played a key role in ECM degradation. miR-221 could inhibit Ets-1 expression. In the mean time, our previous data showed that, under a hyperglycemia condition, endothelial cells overexpressed miR-221 and secreted them into extracellular area via microvesicles. Therefore, the aim of this study is to investigate whether endothelial cells promotes ECM accumulation by secreting miR-221-containing microvesicles into mesangial cells, and the possibility of retarding DN progression by downregulating miR-221 expression.

糖尿病肾病是糖尿病的重要并发症之一。肾小球系膜区细胞外基质的积聚是糖尿病肾病最主要的病理特征，但高血糖导致基质积聚的机制尚未完全明确。系膜细胞的损伤与细胞外基质的积聚密切相关。研究发现，Ets-1/MMPs是系膜细胞调节细胞外基质降解的重要因素，miR-221能调控Ets-1表达。我们的预实验发现，高糖能刺激内皮细胞分泌富含miR-221的微囊泡。因此，本项目以STZ诱导的糖尿病肾病小鼠为研究模型，探讨高糖条件下，肾小球内皮细胞能否通过分泌富含miR-221的微囊泡进入系膜细胞，调节靶细胞内Ets-1/MMPs的表达，阻碍细胞外基质的降解，加重糖尿病肾病，并进一步探讨通过下调miR-221水平延缓糖尿病肾病进程的可能性。

糖尿病肾病是糖尿病的重要并发症之一。肾小球系膜区细胞外基质的积聚是糖尿病肾病最主要的病理特征，但高血糖导致基质积聚的机制尚未完全明确。研究发现，Ets-1/MMPs是系膜细胞调节细胞外基质降解的重要因素，miR-221能调控Ets-1表达。我们的预实验发现，高糖能刺激内皮细胞分泌富含miR-221的微囊泡。本项目以dbdb糖尿病肾病小鼠为研究模型，发现高糖条件下，肾小球内皮细胞分泌富含miR-221的微囊泡，这些微囊泡能够进入系膜细胞，调节靶细胞内Ets-1/MMPs的表达，阻碍细胞外基质的降解，促进细胞外基质在系膜区的积聚，加重糖尿病肾病。使用miR-221的长效抑制剂，可以下调肾组织内miR-221水平，延缓糖尿病肾病发病进程。本项目为糖尿病肾病的治疗提供了新的靶点，对以后的临床治疗有指导意义。