Role of dynamin, synaptojanin, and endophilin in podocyte foot processes
Role of dynamin, synaptojanin, and endophilin in podocyte foot processes
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DOI：
10.1172/jci65289
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发表时间：
2012-12-01
影响因子：
15.9
通讯作者：
Ishibe, Shuta
中科院分区：
文献类型：
--
作者：
Soda, Keita;Balkin, Daniel M.;Ishibe, Shuta
足细胞是一种特殊的细胞，通过其足突在肾小球滤过屏障中发挥着不可或缺的作用。足突形成高度组织化的结构，其破坏会导致肾病综合征。有趣的是，在控制足细胞组织的机制和介导神经元突触发育的机制之间观察到了一些相似之处。动力蛋白、突触蛋白和内亲蛋白是突触小泡回收中的功能伙伴，通过网格蛋白介导的内吞作用和神经元肌动蛋白动力学中的相互关联作用。动力蛋白通过作用于足细胞的肌动蛋白细胞骨架而在维持肾过滤屏障中发挥作用。在这里，我们使用小鼠足细胞中动力蛋白 1 (Dnm1) 和 Dnm2 的条件双敲除来确认动力蛋白在足细胞足突维持中的作用。此外，我们证明，虽然突触蛋白 1 (Synj1) KO 小鼠和内亲蛋白 1 (Sh3gl2)、内亲蛋白 2 (Sh3gl1) 和内亲蛋白 3 (Sh3gl3) 三重 KO 小鼠的胚胎发育基本正常，但这些突变体未能建立正常的过滤屏障，并因足细胞足突异常而表现出严重的蛋白尿 形成。这些结果强烈表明，在肾小球滤过屏障的形成和维持中，神经元突触的内吞作用和肌动蛋白之间的界面上发挥作用的蛋白质网络。
Podocytes are specialized cells that play an integral role in the renal glomerular filtration barrier via their foot processes. The foot processes form a highly organized structure, the disruption of which causes nephrotic syndrome. Interestingly, several similarities have been observed between mechanisms that govern podocyte organization and mechanisms that mediate neuronal synapse development. Dynamin, synaptojanin, and endophilin are functional partners in synaptic vesicle recycling via interconnected actions in clathrin-mediated endocytosis and actin dynamics in neurons. A role of dynamin in the maintenance of the kidney filtration barrier via an action on the actin cytoskeleton of podocytes was suggested. Here we used a conditional double-KO of dynamin 1 (Dnm1) and Dnm2 in mouse podocytes to confirm dynamin's role in podocyte foot process maintenance. In addition, we demonstrated that while synaptojanin 1 (Synj1) KO mice and endophilin 1 (Sh3gl2), endophilin 2 (Sh3gl1), and endophilin 3 (Sh3gl3) triple-KO mice had grossly normal embryonic development, these mutants failed to establish a normal filtration barrier and exhibited severe proteinuria due to abnormal podocyte foot process formation. These results strongly implicate a protein network that functions at the interface between endocytosis and actin at neuronal synapses in the formation and maintenance of the kidney glomerular filtration barrier.