Kidney function requires continuous blood filtration by glomerular capillaries. Disruption of glomerular vascular development or maintenance contributes to the pathogenesis of kidney diseases, but the signaling events regulating renal endothelium development remain incompletely understood. Here, we discovered a novel role of Slit2-Robo signaling in glomerular vascularization. Slit2 is a secreted polypeptide that binds to transmembrane Robo receptors and regulates axon guidance as well as ureteric bud branching and angiogenesis.

We performed Slit2-alkaline phosphatase binding to kidney cryosections from mice with or without tamoxifen-inducible Slit2 or Robo1 and -2 deletions, and we characterized the phenotypes using immunohistochemistry, electron microscopy, and functional intravenous dye perfusion analysis.

Only the glomerular endothelium, but no other renal endothelial compartment, responded to Slit2 in the developing kidney vasculature. Induced Slit2 gene deletion or Slit2 ligand trap at birth affected nephrogenesis and inhibited vascularization of developing glomeruli by reducing endothelial proliferation and migration, leading to defective cortical glomerular perfusion and abnormal podocyte differentiation. Global and endothelial-specific Robo deletion showed that both endothelial and epithelial Robo receptors contributed to glomerular vascularization.

Our study provides new insights into the signaling pathways involved in glomerular vascular development and identifies Slit2 as a potential tool to enhance glomerular angiogenesis.

肾脏功能需要肾小球毛细血管持续过滤血液。肾小球血管发育或维持的破坏导致肾脏疾病的发病机制，但调节肾内皮发育的信号传导事件仍不完全清楚。在这里，我们发现了 Slit2-Robo 信号在肾小球血管化中的新作用。 Slit2 是一种分泌性多肽，可与跨膜 Robo 受体结合并调节轴突引导以及输尿管芽分支和血管生成。

我们对有或没有他莫昔芬诱导的Slit2或Robo1 和 -2缺失的小鼠的肾脏冷冻切片进行了 Slit2 碱性磷酸酶结合，并使用免疫组织化学、电子显微镜和功能性静脉染料灌注分析来表征表型。

在发育中的肾脏血管系统中，只有肾小球内皮对 Slit2 做出反应，而其他肾内皮室则没有反应。出生时诱导的Slit2基因缺失或 Slit2 配体捕获会影响肾发生，并通过减少内皮增殖和迁移来抑制发育中肾小球的血管化，导致皮质肾小球灌注缺陷和足细胞分化异常。整体和内皮特异性 Robo 缺失表明内皮和上皮 Robo 受体均有助于肾小球血管化。

我们的研究为参与肾小球血管发育的信号通路提供了新的见解，并将 Slit2 确定为增强肾小球血管生成的潜在工具。