Integrin-linked kinase (ILK) has been implicated in the pathogenesis of proteinuria and congenital nephrotic syndrome. However, the function of ILK in glomerular podocyte in a physiologic setting remains unknown. In this study, a mouse model was generated in which ILK gene was selectively disrupted in podocytes by using the Cre-LoxP system. Podocyte-specific ablation of ILK resulted in heavy albuminuria, glomerulosclerosis, and kidney failure, which led to animal death beginning at 10 wk of age. Podocyte detachment and apoptosis were not observed at 4 wk of age, when albuminuria became prominent, indicating that they are not the initial cause of proteinuria. Electron microscopy revealed an early foot process effacement, as well as morphologic abnormality, in ILK-deficient podocytes. ILK deficiency caused an aberrant distribution of nephrin and alpha-actinin-4 in podocytes, whereas the localization of podocin and synaptopodin remained relatively intact. Co-immunoprecipitation demonstrated that ILK physically interacted with nephrin to form a ternary complex, and alpha-actinin-4 participated in ILK/nephrin complex formation. Therefore, ILK plays an essential role in specifying nephrin and alpha-actinin-4 distribution and in maintaining the slit diaphragm integrity and podocyte architecture. These results also illustrate that the integrin and slit diaphragm signals in podocytes are intrinsically coupled through an ILK-dependent mechanism.

译文

整联蛋白连接激酶(ILK)已被证明与蛋白尿和先天性肾病综合征的发病机制有关。然而,在生理环境中ILK在肾小球足细胞中的功能仍是未知的。在这项研究中,生成了小鼠模型,其中通过使用Cre-LoxP系统选择性地破坏了足细胞中的ILK基因。 ILK的足细胞特异性消融导致严重的蛋白尿,肾小球硬化和肾衰竭,从而导致动物从10周龄开始死亡。当蛋白尿变得突出时,在4周龄时未观察到足细胞脱离和凋亡,这表明它们不是蛋白尿的最初原因。电子显微镜检查显示,ILK缺陷足细胞有早期足突消失和形态异常。 ILK缺乏引起足细胞中nephrin和α-actinin-4的异常分布,而podocin和synaptopodin的定位仍然相对完整。免疫共沉淀表明ILK与nephrin物理相互作用形成三元复合物,而alpha-actinin-4参与了ILK / nephrin复合物的形成。因此,ILK在指定nephrin和α-actinin-4分布以及维持缝隙隔膜完整性和足细胞结构方面起着至关重要的作用。这些结果还表明,足细胞中的整联蛋白和裂膜信号是通过ILK依赖性机制固有地偶联的。

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