N'Guetta Pierre-Emmanuel Y, McLarnon Sarah R, Tassou Adrien, Geron Matan, Shirvan Sepenta, Hill Rose Z, Scherrer Grégory, O'Brien Lori L
Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Department of Cell Biology and Physiology, UNC Neuroscience Center, Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
bioRxiv. 2024 Mar 7:2023.11.15.567276. doi: 10.1101/2023.11.15.567276.
The kidney functions as a finely tuned sensor to balance body fluid composition and filter out waste through complex coordinated mechanisms. This versatility requires tight neural control, with innervating efferent nerves playing a crucial role in regulating blood flow, glomerular filtration rate, water and sodium reabsorption, and renin release. In turn sensory afferents provide feedback to the central nervous system for the modulation of cardiovascular function. However, the cells targeted by sensory afferents and the physiological sensing mechanisms remain poorly characterized. Moreover, how the kidney is innervated during development to establish these functions remains elusive. Here, we utilized a combination of light-sheet and confocal microscopy to generate anatomical maps of kidney sensory and sympathetic nerves throughout development and resolve the establishment of functional crosstalk. Our analyses revealed that kidney innervation initiates at embryonic day (E)13.5 as the nerves associate with vascular smooth muscle cells and follow arterial differentiation. By E17.5 axonal projections associate with kidney structures such as glomeruli and tubules and the network continues to expand postnatally. These nerves are synapsin I-positive, highlighting ongoing axonogenesis and the potential for functional crosstalk. We show that sensory and sympathetic nerves innervate the kidney concomitantly and classify the sensory fibers as calcitonin gene related peptide (CGRP), substance P, TRPV1, and PIEZO2, establishing the presence of PIEZO2 mechanosensory fibers in the kidney. Using retrograde tracing, we identified the primary dorsal root ganglia, T10-L2, from which PIEZO2 sensory afferents project to the kidney. Taken together our findings elucidate the temporality of kidney innervation and resolve the identity of kidney sympathetic and sensory nerves.
肾脏起着精确调节的传感器作用,通过复杂的协调机制平衡体液成分并滤出废物。这种多功能性需要严格的神经控制,支配性传出神经在调节血流、肾小球滤过率、水和钠的重吸收以及肾素释放方面发挥着关键作用。反过来,感觉传入神经向中枢神经系统提供反馈,以调节心血管功能。然而,感觉传入神经所靶向的细胞和生理传感机制仍未得到充分表征。此外,肾脏在发育过程中如何被神经支配以建立这些功能仍然不清楚。在这里,我们利用光片显微镜和共聚焦显微镜相结合的方法,生成了整个发育过程中肾脏感觉神经和交感神经的解剖图谱,并解析了功能性串扰的建立过程。我们的分析表明,肾脏神经支配在胚胎第(E)13.5天开始,此时神经与血管平滑肌细胞相关联并随着动脉分化而发展。到E17.5时,轴突投射与肾小球和肾小管等肾脏结构相关联,并且该网络在出生后继续扩展。这些神经是突触素I阳性的,突出了正在进行的轴突形成以及功能性串扰的可能性。我们表明,感觉神经和交感神经同时支配肾脏,并将感觉纤维分类为降钙素基因相关肽(CGRP)、P物质、TRPV1和PIEZO2,证实了肾脏中存在PIEZO2机械感觉纤维。通过逆行追踪,我们确定了主要的背根神经节,即T10-L2,PIEZO2感觉传入神经从这里投射到肾脏。综上所述,我们的研究结果阐明了肾脏神经支配的时间性,并解析了肾脏交感神经和感觉神经的身份。