Center for Precision Disease Modeling, Department of Medicine, University of Maryland School of Medicine, 670 West Baltimore Street, Baltimore, MD 21201, USA.
Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, 670 West Baltimore Street, Baltimore, MD 21201, USA.
Cells. 2024 Aug 14;13(16):1350. doi: 10.3390/cells13161350.
In nephrotic syndrome, the podocyte filtration structures are damaged in a process called foot process effacement. This is mediated by the actin cytoskeleton; however, which actins are involved and how they interact with other filtration components, like the basement membrane, remains poorly understood. Here, we used the well-established pericardial nephrocyte-the equivalent of podocytes in flies-knockdown models (RNAi) to study the interplay of the actin cytoskeleton (Act5C, Act57B, Act42A, and Act87E), alpha- and beta-integrin (basement membrane), and the slit diaphragm (Sns and Pyd). Knockdown of an actin gene led to variations of formation of actin stress fibers, the internalization of Sns, and a disrupted slit diaphragm cortical pattern. Notably, deficiency of , which resulted in complete absence of nephrocytes, could be partially mitigated by overexpressing or , suggesting at least partial functional redundancy. Integrin localized near the actin cytoskeleton as well as slit diaphragm components, but when the nephrocyte cytoskeleton or slit diaphragm was disrupted, this switched to colocalization, both at the surface and internalized in aggregates. Altogether, the data show that the interdependence of the slit diaphragm, actin cytoskeleton, and integrins is key to the structure and function of the nephrocyte.
在肾病综合征中，足突细胞的过滤结构会在一个称为足突融合的过程中受损。这是由肌动蛋白细胞骨架介导的；然而，哪些肌动蛋白参与其中，以及它们如何与其他过滤成分（如基底膜）相互作用，仍然知之甚少。在这里，我们使用了经过充分验证的心脏肾细胞（相当于果蝇中的足突细胞）敲低模型（RNAi）来研究肌动蛋白细胞骨架（Act5C、Act57B、Act42A 和 Act87E）、α 和 β 整合素（基底膜）以及裂孔隔膜（Sns 和 Pyd）之间的相互作用。肌动蛋白基因的敲低导致肌动蛋白应力纤维的形成、Sns 的内化和裂孔隔膜皮质模式的破坏发生变化。值得注意的是， 的缺陷导致肾细胞完全缺失，但通过过表达 或 可以部分缓解，这表明至少存在部分功能冗余。整合素定位于肌动蛋白细胞骨架和裂孔隔膜成分附近，但当肾细胞骨架或裂孔隔膜被破坏时，这种定位会切换到共定位，在表面和内部聚集处都有共定位。总的来说，这些数据表明裂孔隔膜、肌动蛋白细胞骨架和整合素之间的相互依赖性是心脏肾细胞结构和功能的关键。
