Role of TRPV1 renal sensory nerves in chronic kidney disease

摘要 慢性肾脏病以不可逆转的肾损害、肾功能恶化和交感神经损害为特征。 激活。去肾神经可改善慢性肾脏病患者的肾功能。这些影响是 部分归因于肾传入(感觉)神经活动(ARNA)的改变。肾感觉神经 肾脏化学环境的感觉变化和反射性调节交感神经流出 来维持肾脏的动态平衡。肾感觉神经在慢性肾功能衰竭发病中的作用 慢性肾脏病的发展没有明确的定义。TRPV1通道在肾感觉神经中表达 TRPV1激动剂辣椒素可增加ARNA和肾交感神经活动。TRPV1 是一种对有害刺激、pH和趋化因子作出反应的非选择性阳离子通道。此外， 持续性炎症是CKD的病理标志，TRPV1通道促进 疼痛和肾病实验模型中的炎症。因此，我的核心假设 在慢性肾脏病中，表达TRPV1的肾传入神经过度活跃和增敏 随后升高肾脏SNA，降低GFR。慢性，表达TRPV1的肾脏 传入纤维感知肾脏细胞因子并促进肾脏炎症，从而进一步 升高肾脏SNA，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-FLOX进行测试 Cre转基因大鼠品系。将采用单单元记录和单细胞转录技术 平行检测TRPV1和非TRPV1表达神经元的同一性并将其与 他们在慢性肾脏病中的活动。光遗传学和转基因大鼠将被用来测试 表达TRPV1的肾脏感觉纤维或TRPV1通道影响肾脏传出SNA和 慢性肾功能不全患者的肾功能最后，将评估肾脏细胞因子诱导的ARNA反应及其 将测试对肾脏SNA和肾脏血流动力学的影响。完成这些目标将1) 识别直接导致肾功能障碍的新的肾感觉神经群 2)为建立一项独立的研究提供支持 该项目侧重于慢性肾脏病等肾脏疾病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.