肾病综合征HDL通过SR-BI调节内皮细胞凋亡和功能的研究

肾病综合征患者存在血管内皮细胞损伤，心血管风险增加。正常HDL可以通过其受体SR-BI激活PI3K/Akt通路，促进内皮细胞增殖迁移并减少其凋亡。肾病时HDL的组分可能发生变化且失去正常功能。肾病综合征HDL对内皮细胞功能和凋亡的影响未有系统研究。我们使用糖尿病 HDL处理人脐静脉内皮细胞，发现内皮细胞SR-BI表达下调，是HDL促内皮细胞增殖迁移功能失调的重要原因，且与Akt相关；在肾病综合征大鼠模型中证实肝脏SR-BI表达显著下降，但未探讨内皮细胞SR-BI表达情况以及此时HDL对内皮细胞功能和凋亡的影响。我们提出假说：肾病综合征HDL通过SR-BI调节PI3K/Akt等通路，导致内皮细胞增殖迁移和抗凋亡功能下降。我们将以人脐静脉内皮细胞、小鼠主动脉内皮细胞和小鼠嘌呤霉素肾病模型等为材料，通过蛋白质组学、转录组分析、腺病毒转染和基因敲除等手段，从分子、细胞、组织及动物水平多方面验证。

Patients with nephrotic syndrome have a high cardiovascular risk due to vascular endothelial cell injury. Previous studies have shown that normal HDL can activate PI3K/Akt pathway through its receptor SR-BI to promote the proliferation and migration of endothelial cells, and to reduce the apoptosis of endothelial cells. In nephrotic patients, the components and function of HDL may change. So far, the relationship between HDL and endothelial cells in nephrotic syndrome has not been elucidated. Our initial findings suggest diabetic HDL is dysfunctional in stimulating endothelial cell proliferation and migration due to down regulation of SR-BI expression, and the expression of SR-BI in nephrotic rats is decreased. However, the effect and mechanism of HDL on endothelial cell proliferation, migration and apoptosis in nephrotic syndrome remain to be further explored. Therefore, we hypothesize that nephrotic syndrome HDL is dysfunctional in stimulating endothelial cell proliferation and migration and preventing apoptosis, in which SR-BI plays an important role, and may be related to the PI3K/Akt signaling pathway. To verify the hypothesis, human umbilical vein endothelial cells, mouse aortic endothelial cells and mouse puromycin nephropathy model will be used as materials, and proteomics, transcriptome analysis, adenovirus transfection and gene knockout and other methods will be used to clarify the underlying mechanisms from molecular, cellular, tissue and system levels.