Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Development. 2023 Nov 15;150(22). doi: 10.1242/dev.201886. Epub 2023 Nov 22.
The intricate vascular system of the kidneys supports body fluid and organ homeostasis. However, little is known about how vascular architecture is established during kidney development. More specifically, how signals from the kidney influence vessel maturity and patterning remains poorly understood. Netrin 1 (Ntn1) is a secreted ligand that is crucial for vessel and neuronal guidance. Here, we demonstrate that Ntn1 is expressed by Foxd1+ stromal progenitors in the developing mouse kidney and conditional deletion (Foxd1GC/+;Ntn1fl/fl) results in hypoplastic kidneys with extended nephrogenesis. Wholemount 3D analyses additionally revealed the loss of a predictable vascular pattern in Foxd1GC/+;Ntn1fl/fl kidneys. As vascular patterning has been linked to vessel maturity, we investigated arterialization. Quantification of the CD31+ endothelium at E15.5 revealed no differences in metrics such as the number of branches or branch points, whereas the arterial vascular smooth muscle metrics were significantly reduced at both E15.5 and P0. In support of our observed phenotypes, whole kidney RNA-seq revealed disruptions to genes and programs associated with stromal cells, vasculature and differentiating nephrons. Together, our findings highlight the significance of Ntn1 to proper vascularization and kidney development.
肾脏复杂的血管系统支持体液和器官的内稳态。然而，人们对肾脏发育过程中血管结构是如何建立的知之甚少。更具体地说，肾脏发出的信号如何影响血管成熟和模式化仍然知之甚少。Netrin 1（Ntn1）是一种重要的血管和神经元导向的分泌配体。在这里，我们证明 Ntn1 由发育中的小鼠肾脏中的 Foxd1+基质祖细胞表达，条件性缺失（Foxd1GC/+;Ntn1fl/fl）导致肾脏发育不全，肾发生延长。全胚胎 3D 分析还显示 Foxd1GC/+;Ntn1fl/fl 肾脏中失去了可预测的血管模式。由于血管模式与血管成熟有关，我们研究了动脉形成。在 E15.5 时对 CD31+内皮细胞的定量分析显示，分支或分支点的数量等指标没有差异，而动脉血管平滑肌的指标在 E15.5 和 P0 时均显著降低。为了支持我们观察到的表型，全肾 RNA-seq 显示与基质细胞、血管和分化肾单位相关的基因和程序受到干扰。综上所述，我们的研究结果强调了 Ntn1 对血管生成和肾脏发育的重要性。
