Statins通过Rac1保护嘌呤毒素氨基核苷诱导的足细胞表型改变

The prevention and treatment of chronic kidney disease is a worldwide public health problem. In recent years, clinical studies found that statins have renoprotective effects, basic research has been initially clear protective effect of statins play multi-effect through the inhibition of small G proteins of Rac, Rho, in the kidney. Statins protective role and mechanism of action for the maintenance of normal glomerular filtration rate podocytes is also poorly understood. At the same time, recent studies have found that sustained Rac1 activation energy lead to phenotypic changes of podocytes and foot process fusion, apoptosis, leading to glomerular fibrosis.In this study, intended by the body of animal model studies Rac1 in his statins protect the foot cell phenotype change by in vitroexperimental study Rac1 to the process of role and the role of mechanisms; statins and foot cell movement ability, cytoskeletonrearrangement influence and role mechanism. This pleiotropic mechanism of statin organ protection by the comprehensiveunderstanding of this study will provide a theoretical basis to provide new ideas for further study of chronic kidney diseaseprevention and control strategies.

慢性肾脏病的防治是世界范围内的公共卫生问题。近年来的临床研究发现他汀具有肾脏保护作用，通过基础研究已经初步明确他汀通过抑制小G蛋白Rac、Rho等在肾脏发挥多效保护作用。但是他汀对维护正常肾小球滤过功能的足细胞的保护作用和作用机制还知之甚少。同时，最近的研究发现Rac1持续活化能导致足细胞的表型改变，如足突融合、细胞凋亡等，进而导致肾小球纤维化。本研究拟通过在体动物模型研究Rac1在他汀保护足细胞表型改变以过程中的作用和作用机制；通过体外细胞实验研究Rac1在他汀及对足细胞运动能力、细胞骨架重排的影响和作用机制。通过本研究将对全面认识他汀的器官保护这一多效性作用机制提供理论依据，对进一步研究慢性肾脏病的防治策略提供新的思路。

慢性肾脏病的防治是世界范围内的公共卫生问题。近年来的研究发现，他汀能够通过多效性作用对多种肾脏实验模型起到保护作用。他汀对肾小球足细胞的作用还未被透彻研究。本研究的目的即在于通过体外和体内观察阿托伐他汀对嘌呤毒素氨基核苷（PAN）诱导的大鼠足细胞表型改变的作用及其机制。大鼠一次性腹腔注射PAN诱导肾病综合征模型，PAN导致的大量蛋白尿，低蛋白血症和高脂血症能够被阿托伐他汀所抑制。他汀能够抑制PAN所诱导的大鼠足细胞表型改变如足突融合、足细胞凋亡等。通过western blot法证实他汀能够抑制PAN所致足细胞裂孔隔膜蛋白nephrin和podocin的表达。在PAN肾病大鼠模型中，肾小球内的活性氧水平明显上升，NADPH氧化酶家族成员NOX4表达明显上调，Rac1和RhoA的活性增高，而阿托伐他汀能够抑制上述改变。这些研究结果提示，在PAN大鼠模型中，阿托伐他汀能通过抑制Rac1活性减轻ROS介导的足细胞损伤。为临床足细胞病提供了治疗的新思路。