Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA.
Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA.
Development. 2023 Nov 15;150(22). doi: 10.1242/dev.201884. Epub 2023 Nov 22.
The kidney vasculature has a complex architecture that is essential for renal function. The molecular mechanisms that direct development of kidney blood vessels are poorly characterized. We identified a regionally restricted, stroma-derived signaling molecule, netrin 1 (Ntn1), as a regulator of renal vascular patterning in mice. Stromal progenitor (SP)-specific ablation of Ntn1 (Ntn1SPKO) resulted in smaller kidneys with fewer glomeruli, as well as profound defects of the renal artery and transient blood flow disruption. Notably, Ntn1 ablation resulted in loss of arterial vascular smooth muscle cell (vSMC) coverage and in ectopic SMC deposition at the kidney surface. This was accompanied by dramatic reduction of arterial tree branching that perdured postnatally. Transcriptomic analysis of Ntn1SPKO kidneys revealed dysregulation of vSMC differentiation, including downregulation of Klf4, which we find expressed in a subset of SPs. Stromal Klf4 deletion similarly resulted in decreased smooth muscle coverage and arterial branching without, however, the disruption of renal artery patterning and perfusion seen in Ntn1SPKO. These data suggest a stromal Ntn1-Klf4 axis that regulates stromal differentiation and reinforces stromal-derived smooth muscle as a key regulator of renal blood vessel formation.
肾脏的脉管系统具有复杂的结构，这对于肾脏功能至关重要。然而，指导肾脏血管发育的分子机制还没有得到很好的描述。我们发现，神经导向因子 1（netrin 1，Ntn1）是一种局限于区域的、基质衍生的信号分子，可作为调节小鼠肾脏血管模式形成的因子。基质祖细胞（stromal progenitor，SP）特异性 Ntn1 缺失（Ntn1SPKO）导致肾脏变小，肾小球数量减少，肾动脉严重缺陷和短暂的血流中断。值得注意的是，Ntn1 缺失导致动脉血管平滑肌细胞（vascular smooth muscle cell，vSMC）覆盖丧失，并在肾脏表面异位沉积 SMC。这伴随着动脉树分支的显著减少，这种情况在出生后持续存在。Ntn1SPKO 肾脏的转录组分析显示 vSMC 分化失调，包括 Klf4 的下调，我们发现 Klf4 在一小部分 SP 中表达。然而，基质 Klf4 缺失并没有像 Ntn1SPKO 那样导致动脉分支的破坏和肾脏动脉模式的破坏，也没有导致动脉分支的破坏和肾脏动脉模式的破坏。这些数据表明，基质 Ntn1-Klf4 轴调节基质分化，并加强基质衍生的平滑肌作为肾脏血管形成的关键调节因子。
