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

健康和高血压小鼠肾皮质的感觉神经支配

• 批准号: 10215236
• 负责人: Roman Tyshynsky
• 金额: $ 3.34万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10215236
• 关键词: Ablation; Affect; Afferent Neurons; Anatomy; Antihypertensive Agents; Automobile Driving; Cardiovascular system; Chemicals; Clinical Trials; DOCA; Data; Denervation; Development; Devices; Disease; Efferent Neurons; Excretory function; Family suidae; Fiber; Filtration; Glomerular Filtration Rate; Goals; Health; Heterogeneity; Hypertension; Image; Immunofluorescence Immunologic; Individual; Inflammation; Kidney; Knowledge; Literature; Maintenance; Maps; Measures; Mediating; Modeling; Mus; Nature; Nerve; Nerve Fibers; Neuroanatomy; Neurons; Neurosciences; Nonpharmacologic Therapy; Outcome; Patients; Peripheral; Physiological; Physiology; Play; Population; Pre-Clinical Model; Procedures; Process; Proteins; Protocols documentation; Rattus; Reflex action; Regulation; Renal Blood Flow; Renal function; Renal pelvis; Renovascular Hypertension; Reporter; Reporting; Research; Resistance; Resistant Hypertension; Rodent Model; Role; Sensory; Sodium; Sodium Chloride; TRPV1 gene; Techniques; Testing; Tissues; Training; afferent nerve; base; career; experience; experimental study; falls; hypertension treatment; improved; kidney cortex; nerve supply; neuroregulation; normotensive; optogenetics; pressure; promoter; response; salt sensitive hypertension

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.

项目摘要 肾神经的基于器械的消融已经成为一种非药物治疗，用于患有肾功能不全的患者。 难治性高血压最近的临床试验表明，它可以降低大多数人的动脉压。 难治性高血压患者，但介导这种效应的神经元机制尚不清楚。 该手术非选择性地破坏肾脏的感觉神经和交感神经，尽管其 一些患者经历的是动脉压的上升，而不是下降。对此的一种解释 反应的异质性是不同的肾神经群在动脉调节中起不同的作用， 压力例如，这些肾交感神经和感觉神经在多大程度上有助于 高血压尚不清楚。目前的教条是，肾感觉神经纤维主要位于血管壁中。 肾盂反射性抑制交感神经这与观察结果一致， 这些神经在某些试验中会增加动脉压。然而，我们最近发现，肾感觉 神经还反射性地兴奋交感神经，伴随着动脉压和交感神经压的降低。 DOCA-盐大鼠肾脏炎症模型中感觉特异性化学肾脏去神经支配后的活性 和高血压。感觉神经在肾脏内的解剖分布尚未被广泛研究。 研究，我已经观察到丰富的感觉纤维定位附近的皮质肾小球的小鼠，大鼠， 猪肾的研究基本上没有报道。在我们对这一问题的程度和目标的了解方面， 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调查这些差距，两个互补的目标，在两个健康的 和DOCA盐高血压小鼠。首先，我将使用组织清除程序，然后是 免疫荧光法测定肾小球感觉纤维的神经支配程度。第二，我会 使用光遗传学刺激肾皮质内的这些感觉纤维，以确定它们在 控制动脉血压和肾功能根据初步结果和现有文献，我的中心 假设感觉纤维支配皮质肾小球并通过交感神经调节肾功能， 兴奋性反射，其在DOCA-盐HTN中被放大。这些实验的结果将带来更多 完整了解感觉肾神经解剖和感觉纤维对肾血管的影响， 高血压如果这些位于皮层的感觉纤维被证明在交感神经兴奋中起作用， 以这种方式，它们将代表一种有希望的消融靶点，以增强肾动脉的抗高血压作用。 去神经疗法这进一步推进了我们的长期目标，即扩大我们对肾神经作用的理解。 在高血压的发展和维持中，帮助引导消融和神经调节肾神经- 基于治疗。