足细胞损伤与脱落是高血压肾损害的早期细胞事件，但其发生机制未明。Zyxin是黏着斑上的压力感受器，可调控应力纤维重构。我们的前期研究发现，在高机械应力作用下，足细胞内zyxin表达下降，同时伴有衔接蛋白α-actinin-4下降，动力蛋白非肌肉肌球蛋白IIA（NMIIA）活性增加，而过表达zyxin后可逆转上述变化。据此我们提出假说：在高血压所致的肾小球内高压力状态下，足细胞内zyxin表达下降，可使募集到应力纤维上的α-actinin-4减少，导致与其竞争应力纤维结合位点的NMIIA表达增加并活化，引起应力纤维重构，足细胞迁移力增加而致其脱落。本课题拟以微流器官芯片技术培养的人足细胞系和足细胞特异性基因敲除小鼠模型为研究对象，深入探讨zyxin调控应力纤维重构在高血压肾损害中的作用及机制，期望为临床延缓高血压肾损害的进展提供新思路。

Podocyte injury and detachment are the early cell events in hypertensive nephropathy. However, the molecular mechanism is not fully understood. Zyxin is a mechanosensor belongs to focal adhesions, and it plays an important role in the reconstitution of actin stress fibers. Our preliminary data showed that high mechanical forces induced the downregulation of zyxin, which accompanied by the decrease of actin adaptor protein α-actinin-4, and activation of non-muscle myosin IIA (NMIIA). Overexpression of zyxin reversed the above changes. According to these results, we proposed our hypothesis: Upon the persistent high pressure in the glomeruli, the expression of zyxin is downregulated, which induces the decreased recruitment of α-actinin-4 to the stress fibers, and the increased expression and activation of NMIIA which competes binding sites with α-actinin-4 on stress fibers, leads to the reconstitution of stress fibers and then results in podocytes hypermotility and detachment. Based on this hypothesis, we will investigate the role of zyxin in hypertensive nephropathy and explore the downstream molecular mechanisms by using conditional immortalized human podocyte in vitro, podocyte specific conditional knockout mice in vivo. This might provide a new idea for delaying the progression of hypertensive nephropathy.