Tufro Alda
Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, PO Box 208064, New Haven, CT, 06520-8064, USA,
Pediatr Nephrol. 2014 Apr;29(4):751-5. doi: 10.1007/s00467-013-2743-x. Epub 2014 Jan 26.
Semaphorin3a (sema3a), a member of class 3 semaphorins, is a guidance protein that regulates angiogenesis, branching morphogenesis, axon growth, and cell migration, and has pleiotropic roles on organogenesis, immune response, and cancer. Sema3a is secreted by podocytes and is required for normal kidney patterning and glomerular filtration barrier development. We recently discovered that after completion of kidney development, Sema3a gain-of-function in podocytes leads to proteinuric glomerular disease in mice. Excess sema3a causes foot process effacement, glomerular basement lamination, and endothelial damage in vivo, and disrupts cell autonomously podocyte shape by down-regulating nephrin and inhibiting αvβ3 integrin. We identified a novel direct interaction between nephrin and plexinA1, the sema3a signaling receptor. Nephrin-plexinA1 interaction links the slit-diaphragm signaling complex to extracellular sema3a signals. Hence, sema3a functions as an extracellular negative regulator of the structure and function of the glomerular filtration barrier.
信号素3a（Sema3a）是3类信号素成员之一，是一种指导蛋白，可调节血管生成、分支形态发生、轴突生长和细胞迁移，并且在器官发生、免疫反应和癌症方面具有多效性作用。Sema3a由足细胞分泌，是正常肾脏模式形成和肾小球滤过屏障发育所必需的。我们最近发现，在肾脏发育完成后，足细胞中Sema3a功能获得会导致小鼠出现蛋白尿性肾小球疾病。过量的Sema3a在体内会导致足突消失、肾小球基底膜分层和内皮损伤，并通过下调nephrin和抑制αvβ3整合素自主破坏足细胞形状。我们确定了nephrin与信号素3a信号受体丛状蛋白A1之间存在一种新的直接相互作用。Nephrin-丛状蛋白A1相互作用将裂孔隔膜信号复合物与细胞外Sema3a信号联系起来。因此，Sema3a作为肾小球滤过屏障结构和功能的细胞外负调节因子发挥作用。
