The Sensory Innervation of the Renal Cortex of Healthy and Hypertensive Mice

项目总结 基于设备的肾神经消融术已经成为一种非药物治疗方法，用于治疗慢性肾功能衰竭患者 难治性高血压。最近的临床试验表明，它能降低大多数人的动脉压 患有难治性高血压的患者，但调节这种效应的神经机制尚不清楚。 这一过程非选择性地破坏了肾脏的感觉神经和交感神经，尽管它 承诺，一些患者的动脉压会上升，而不是下降。对此有一种解释 反应的异质性是不同群体的肾神经在动脉调节中扮演不同的角色 压力。例如，这些肾交感神经和感觉神经在多大程度上对 高血压目前还不清楚。目前的学说是，肾感觉神经纤维主要位于 肾盆和反射性抑制交感神经。这与观察到的消融是一致的。 在一些试验中，这些神经会增加动脉压。然而，我们最近证实了肾脏感受器 神经也反射性地兴奋交感神经，使动脉压和交感加压降低。 DOCA-SALT大鼠肾脏炎症模型中感觉特异性化学去神经后的活动 还有高血压。肾内感觉神经的解剖分布还不是很广泛。 我观察到小鼠、大鼠和小鼠皮质小球附近有丰富的感觉纤维定位。 猪肾在很大程度上仍未报告。我们对艾滋病的范围和目标的了解仍然存在差距 肾皮质的这种感觉神经支配，以及皮质感觉纤维在调节 交感神经活动。我的项目旨在通过两个相辅相成的目标来调查这些差距 和DOCA-盐性高血压小鼠。首先，我将使用组织清除透明程序，然后是 免疫荧光法测定感觉纤维支配肾小球的程度。第二，我会 利用光遗传学刺激肾皮质内的这些感觉纤维，以确定它们在其中所起的作用 控制动脉压和肾功能。根据初步结果和当前文献，我的中央 假说认为，感觉纤维支配皮质小球，并通过交感神经调节肾功能。 兴奋性反射，在DOCA-SALT HTN中放大。这些实验的结果将导致更多的 肾感觉神经解剖及感觉纤维对肾血管的影响 高血压。如果这些位于大脑皮层的感觉纤维被证明在交感兴奋中起作用 以这种方式，它们将是一个有希望的消融靶点，以增强肾脏的降压效果。 去神经疗法。这进一步促进了我们扩大对肾神经作用的理解的长期目标。 在高血压的发展和维持中帮助指导消融和神经调节的肾神经- 以治疗为基础。

PROJECT SUMMARY Device-based ablation of renal nerves has emerged as a non-pharmacological therapy for patients with treatment-resistant hypertension. Recent clinical trials demonstrate it decreases arterial pressure in most patients with treatment-resistant hypertension, but the neuronal mechanisms mediating this effect are unknown. This procedure non-selectively destroys both the sensory and sympathetic nerves of the kidney, and despite its promise, some patients experience a rise, rather than a fall in arterial pressure. One explanation for this heterogeneity of responses is that different populations of renal nerves play different roles in regulation of arterial pressure. For example, the extent to which these renal sympathetic and sensory nerves contribute to hypertension is unclear. The current dogma is that renal sensory nerve fibers are located mainly in the wall of the renal pelvis and reflexively inhibit sympathetic nerves. This is consistent with the observation that ablation of these nerves increases arterial pressure in some trials. However, we recently established that renal sensory nerves also reflexively excite sympathetic nerves, with a decrease in arterial pressure and sympathetic pressor activity following a sensory-specific chemical renal denervation in the DOCA-salt rat model of renal inflammation and hypertension. The anatomical distribution of sensory nerves within the kidney has not been extensively studied, and I have observed abundant sensory fiber localization near the cortical glomeruli of mouse, rat, and pig kidney that remains largely unreported. There remains a gap in our knowledge of the extent and targets of this sensory innervation of the renal cortex, and the function of cortical sensory fibers in the modulation of sympathetic activity. My project aims to investigate these gaps with two complementary goals in both healthy and DOCA-salt hypertensive mice. First, I will use the tissue-clearing CLARITY procedure, followed by immunofluorescence to determine the extent of the innervation of glomeruli by sensory fibers. Second, I will stimulate these sensory fibers within the renal cortex using optogenetics to determine the roles they play in controlling arterial pressure and kidney function. Based on preliminary results and current literature, my central hypothesis is that sensory fibers innervate cortical glomeruli and regulate renal function through a sympatho- excitatory reflex, which is amplified in DOCA-salt HTN. The results of these experiments will lead to a more complete understanding of sensory renal neuroanatomy and the influences sensory fibers on renovascular hypertension. Should these sensory fibers located in the cortex prove to function in a sympatho-excitatory manner, they would represent a promising target for ablation to enhance the anti-hypertensive effects of renal denervation therapies. This furthers our long-term goal of expanding our understanding of the role of renal nerves in the development and maintenance of hypertension to help guide ablative and neuromodulatory renal nerve- based treatments.