Reidy Kimberly J, Villegas Guillermo, Teichman Jason, Veron Delma, Shen Wa, Jimenez Juan, Thomas David, Tufro Alda
Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA.
Development. 2009 Dec;136(23):3979-89. doi: 10.1242/dev.037267.
Semaphorin3a (Sema3a), a chemorepellant guidance protein, plays crucial roles in neural, cardiac and peripheral vascular patterning. Sema3a is expressed in the developing nephron, mature podocytes and collecting tubules. Sema3a acts as a negative regulator of ureteric bud branching, but its function in glomerular development has not been examined. Here we tested the hypothesis that Sema3a regulates glomerular vascular development using loss- and gain-of-function mouse models. Sema3a deletion resulted in defects in renal vascular patterning, excess endothelial cells within glomerular capillaries, effaced podocytes with extremely wide foot processes and albuminuria. Podocyte Sema3a overexpression during organogenesis resulted in glomerular hypoplasia, characterized by glomerular endothelial cell apoptosis, delayed and abnormal podocyte foot process development, a complete absence of slit diaphragms and congenital proteinuria. Nephrin, WT1 and VEGFR2 were downregulated in Sema3a-overexpressing kidneys. We conclude that Sema3a is an essential negative regulator of endothelial cell survival in developing glomeruli and plays a crucial role in podocyte differentiation in vivo. Hence, a tight regulation of Sema3a dosage is required for the establishment of a normal glomerular filtration barrier.
信号素3a（Sema3a）是一种化学排斥导向蛋白，在神经、心脏和外周血管模式形成中发挥关键作用。Sema3a在发育中的肾单位、成熟足细胞和集合小管中表达。Sema3a作为输尿管芽分支的负调节因子，但其在肾小球发育中的功能尚未得到研究。在这里，我们使用功能丧失和功能获得小鼠模型测试了Sema3a调节肾小球血管发育的假说。Sema3a缺失导致肾血管模式形成缺陷、肾小球毛细血管内内皮细胞过多、足细胞消失且足突极宽以及蛋白尿。器官发生过程中足细胞Sema3a过表达导致肾小球发育不全，其特征为肾小球内皮细胞凋亡、足细胞足突发育延迟和异常、完全缺乏裂孔隔膜以及先天性蛋白尿。在Sema3a过表达的肾脏中，Nephrin、WT1和VEGFR2表达下调。我们得出结论，Sema3a是发育中的肾小球内皮细胞存活的重要负调节因子，并且在体内足细胞分化中起关键作用。因此，建立正常的肾小球滤过屏障需要严格调节Sema3a的剂量。
