ASPP2调控老年自发性高血压大鼠AngII诱导的肾小球足细胞自噬机制的研究

肾小球足细胞损伤和丢失，在高血压肾硬化发病机制中起重要作用。研究结果显示，足细胞中自噬途径的异常是足细胞病变的主要原因之一；高血压时肾组织局部AngII水平增高，细胞实验显示AngII诱导肾小球足细胞(CIMPs)自噬。我们的结果：ASPP2可通过与ATG16竞争结合ATG5/ATG12，阻止ATG16/ATG5/ATG12复合体形成，抑制自噬；并发现自发性高血压大鼠（SHR）肾组织中ASPP2高表达。因此，我们假设：高血压时肾小球足细胞中ASPP2高表达，有可能通过这一途径下调AngII诱导的自噬，减轻足细胞损伤，维持细胞稳态。本课题以SHR、CIMPs为模型，采用免疫沉淀、基因转染、电镜等方法，揭示随增龄SHR肾组织ASPP2表达及定位的变化、AngII水平的变化、自噬活性的变化，CIMPs中ASPP2对自噬的调控、AngII对ASPP2的影响，课题结果将深入揭示高血压肾损伤新机制。

The injury and loss of glomerular podocytes play an important role in the pathogenesis of hypertensive nephrosclerosis. Previous studies indicate that the abnormality in autophagy pathway of glomerular podocytes is one of the main causes of podocyte lesions. As the level of hypertension intrarenal angiotensin II(AngII) increases, cell experiments show that AngII induces the autophagy of conditionally immortalized mouse podocytes(CIMPs). Our latest results demonstrated that ASPP2, competing with ATG16 to bind ATG5/ATG12, prevents the formation of ATG16/ATG5/ATG12, thereby inhibiting autophagy; we also discovered high ASPP2 expression in the renal tissue of spontaneously hypertensive rats (SHR). Therefore, we hypothesis that the high level of ASPP2 expression in glomerular podocytes during hypertension is likely to decrease AngII-induced autophagy through the above-mentioned pathway, which would maintain cell homeostasis and alleviat podocyte injury. This project uses SHR and CIMPs as its model, and adopts immunoprecipitation, gene transfection, electron microscopy, et al as its methods. It will evaluate the age-related changes in the expression and localization of ASPP2, changes in the level of AngII, and changes in autophagic activity in the renal tissue of SHR; it will also assess the effect of ASPP2 regulation of autophagy and the influence of AngII on ASPP2 function in CIMPs. The results will reveal the new mechanism of hypertensive renal injury.