Role of TRPV1 renal sensory nerves in chronic kidney disease

摘要 CKD的特征在于不可逆的肾损伤、肾功能恶化和交感神经系统损伤。 activation.去肾神经支配改善CKD患者的肾功能这些影响是 部分归因于改变的肾传入（感觉）神经活动（ARNA）。肾感觉神经 感觉改变肾脏的化学环境并反射性地调节交感神经流出 来维持肾脏的稳态肾感觉神经在肾性脑病中的致病作用 CKD的发展定义不明确。TRPV1通道在肾感觉神经中表达 TRPV1激动剂辣椒素增加ARNA和肾交感神经活性。TRPV1 是一种非选择性阳离子通道，对有害刺激、pH和趋化因子作出反应。此外，委员会认为， 持续性炎症是CKD的病理标志，TRPV1通道促进 在疼痛和肾病的实验模型中的炎症。因此，我的核心假设 表达TRPV1的肾传入神经在CKD中过度活跃和敏感， 随后升高肾SNA并降低GFR。长期而言，表达TRPV1的肾脏 传入纤维感知肾细胞因子，并促进肾炎症， 提高肾脏SNA并减少GFR恶化的CKD进展。这一假设将是 使用"最先进的"神经生理学方法和新型TRPV1-flox和TRPV1- Cre转基因大鼠品系。将采用单单位记录和单细胞转录组学， 平行检查TRPV1和非TRPV1表达神经元的身份，并将它们与 在CKD中的作用光遗传学和转基因大鼠将被用来测试的程度， 表达TRPV1的肾感觉纤维或TRPV1通道影响肾传出SNA， CKD的肾功能。最后，将评估肾烟碱诱发的ARNA反应，并将其 将测试对肾SNA和肾血流动力学的影响。实现这些目标将：（1） 鉴定直接导致肾功能障碍新的肾感觉神经群 和炎症，2）为建立一个独立的研究提供支持 该项目专注于肾脏疾病（如CKD）中肾功能的神经控制。

ABSTRACT CKD is characterized by irreversible kidney damage, worsening renal function, and sympathetic activation. Renal nerve denervation improves kidney function in CKD patients. These effects are partly attributed to altered renal afferent (sensory) nerve activity (ARNA). Renal sensory nerves sense changes in the chemical milieu of the kidney and reflexively modulate sympathetic outflow to maintain kidney homeostasis. The pathogenic contribution of renal sensory nerves in the development of CKD is poorly defined. TRPV1 channels are expressed in renal sensory nerves and the TRPV1 agonist capsaicin increases ARNA and renal sympathetic nerve activity. TRPV1 is a nonselective cation channel that responds to noxious stimuli, pH, and chemokines. Moreover, persistent inflammation is a pathologic hallmark of CKD and TRPV1 channels promote inflammation in experimental models of pain and nephropathy. Therefore, my core hypothesis is that TRPV1-expressing renal afferent nerves are overactive and sensitized in CKD to subsequently elevate renal SNA and reduce GFR. Chronically, TRPV1-expressing renal afferent fibers sense renal cytokines and contribute to renal inflammation that further elevate renal SNA and reduces GFR–worsening CKD progression. This hypothesis will be tested using “state-of-the-art” neurophysiological approaches and novel TRPV1-flox and TRPV1- Cre transgenic rat lines. Single unit recordings and single-cell transcriptomics will be employed in parallel to examine the identity of TRPV1 and non-TRPV1 expressing neurons and link them with their activity in CKD. Optogenetics and transgenic rats will be used to test the extent by which TRPV1-expressing renal sensory fibers or TRPV1 channels influence renal efferent SNA and renal function in CKD. Lastly, renal cytokine-evoked ARNA responses will be evaluated and their impact on renal SNA and renal hemodynamics will be tested. Completion of these aims will 1) identify novel renal sensory nerve populations that directly contribute to renal dysfunction and inflammation in CKD and 2) provide support for establishing an independent research program focused on the neural control of kidney function in renal disease such as CKD.