黄芪汤调控MAGI2/Rap1信号通路减缓糖尿病肾病足细胞损伤的机制研究

Diabetic nephropathy (DN) is the leading cause of death and disability in diabetic patients. The podocyte injury plays a key role in the pathogenesis of diabetic nephropathy. It has demonstrated that MAGI2 (membrane-associated guanylate kinase inverted 2), a podocyte slit diaphragm (SD) protein, is highly expressed in podocyte and closely related to its injury and is regulated by the transcription factor WT1. Our previous study found that MAGI2 could reduce the detachment and injury of normal podocytes by activating the small GTPase Rap1 signaling pathway. In addition there was a downregulation of MAGI2 expression in the glomeruli of DN mouse, and the low expression of MAGI2 could be reversed by Huangqi decoction, however the specific mechanism has not been revealed. Therefore, this study will hypothesize that Huangqi decoction may alleviate podocyte injury through the upregulation of MAGI2 and the activation of Rap1 signaling pathway. In this project we will study the protective role and molecular mechanism of MAGI2 on podocyte injury by methods of cell biology, animal histology and molecular pharmacology in diabetic nephropathy, in which we will use the models of db/db mouse and the podocyte stimulated with high glucose. To further explore the molecular mechanism of Huangqi decoction to reduce podocyte injury by regulating MAGI2/Rap1 signaling pathway in diabetic nephropathy, we will further use different concentrations of Huangqi decoction in the experiment, thus providing scientific theory and experimental basis for clinical prevention and treatment of Huangqi decoction in diabetic nephropathy.

糖尿病肾病（DN）是糖尿病患者致死致残的重要原因，足细胞损伤对DN发病至关重要。目前已证实足细胞裂孔隔膜蛋白MAGI2，受转录因子WT1调控并在足细胞中高表达，与其损伤关系密切。我们前期研究发现在正常足细胞中，MAGI2能通过活化Rap1信号通路减轻细胞损伤和脱落，同时在DN小鼠肾小球中亦存在MAGI2表达下调，而黄芪汤能逆转MAGI2低表达并减缓DN足细胞损伤，但具体机制尚未揭示。据此我们提出黄芪汤可能通过上调MAGI2，激活Rap1信号通路，从而减缓DN足细胞损伤。故本项目拟通过db/db小鼠及高糖诱导人足细胞损伤模型，采用细胞生物学、动物组织学、分子药理学等技术研究MAGI2对DN足细胞损伤的保护作用及分子机制，并进一步予不同剂量黄芪汤干预，深入探究黄芪汤通过调控MAGI2/Rap1信号途径减轻DN足细胞损伤的分子机制，上述研究有望为黄芪汤临床防治DN提供新的科学理论和实验依据。

糖尿病肾病（DN）是糖尿病患者致死致残的重要原因，足细胞损伤对DN发病至关重要。目前已证实足细胞裂孔隔膜蛋白MAGI2，在足细胞中高表达，与其损伤关系密切。我们前期研究发现在DN小鼠肾小球中亦存在MAGI2表达下调，而黄芪汤能逆转MAGI2低表达并减缓DN足细胞损伤，但具体机制尚未揭示。为深入研究DN足细胞损伤以及黄芪汤改善足细胞损伤的分子机制，我们通过db/db小鼠及高糖诱导人足细胞损伤模型，采用细胞生物学、动物组织学、分子药理学等技术研究MAGI2对DN足细胞损伤的保护作用及分子机制，并进一步予不同剂量黄芪汤干预，深入探究黄芪汤通过调控MAGI2/Rap1信号途径减轻DN足细胞损伤的分子机制。结果显示，MAGI2缺乏参与了DN足细胞损伤，高糖可抑制WT1、MAGI2表达及下游Rap1活性，而黄芪汤能上调WT1、MAGI2表达，及激活Rap1及下游信号通路在DN足细胞损伤中的发挥保护作用。本项目阐明了MAGI2在DN足细胞损伤中的保护作用及分子机制，明确了黄芪汤通过上调WT1、MAGI2表达，及激活Rap1信号通路在DN足细胞损伤中的保护作用及作用靶点，为DN的诊断和治疗提供了新的思路和策略。