肾脏megalin调控树突状细胞介导的Tregs激活在动脉粥样硬化中的作用及机制研究

动脉粥样硬化（AS）是致死率最高的心血管疾病。AS的病变形成过程由多器官多系统共同作用，其中肾脏是AS的重要参与者，然而肾脏对AS的作用及机制尚未阐明。Megalin是肾脏特异性分子，参与物质重吸收并调控肾内微环境。我们前期研究证实抑制小鼠megalin可显著减少AS，但其机制尚不明确。免疫-炎症系统参与AS的形成，其中免疫耐受性树突状细胞（tDCs）激活Tregs，后者对AS起保护作用。我们的前期实验发现，抑制megalin可改变肾内炎症微环境，促进Foxp3+T细胞的增生，同时DCs上CD80的表达减少而IDO表达升高，提示tDCs及Tregs的形成。本研究提出假设，megalin通过调控tDCs介导的Tregs激活影响AS的形成。本研究构建肾脏特异性megalin敲除小鼠并建立AS模型，探索megalin对AS及Tregs的调控作用及机制，为理解并治疗AS提供新的理论基础和潜在靶点。

Atherosclerotic cardiovascular disease is the leading cause of death worldwide. The formation of atherosclerosis is coordinated by multiple organs and systems. Kidney is one major participant in atherogenesis, since kidney injury leads to the provocation of a vast array of proatherogenic elements and accelerates the development and progression of the disease. However, the exact role of kidney in atherosclerosis is still sealed. Megalin is predominantly expressed in kidney and involved in uptake of glomerular-filtered substances and regulation of intrarenal microenvironment. Previous study has found that inhibition of megalin reduces atherosclerosis, but the mechanisms are unknown. Hyperactivation of the immune-inflammatory system plays a pivotal role in atherogenesis. It is well documented that tolerogenic dendritic cells (tDCs) contributes to the activation of Tregs which ameliorate atherosclerosis. Our pilot studies showed that inhibition of megalin altered intrarenal inflammatory status, augmented Foxp3+ T cells, suppressed CD80 and promoted IDO expression in DCs, indicating the generation of tDCs and Tregs. We proposed that megalin contributes to atherosclerosis through modulating tDCs-induced Tregs activation. In this project, we will use kidney-specific megalin knockout mice to investigate the regulatory role of megalin in Tregs and atherosclerosis, gaining the notion of the mechanism and providing promising therapeutic targets for atherosclerosis.