Control of Renal Inflammation in Hypertension

项目总结 到2025年，全球估计将有16亿人患有高血压。这一估计可能更高 考虑到最近修改的高血压指南，其中包括数百万额外的患者。是什么 令人担忧的是，几乎20%的高血压患者对目前的治疗方法有抵抗力。更好地理解 为了确定新的高血压发病机制，需要了解高血压发病的潜在机制。 和有效的治疗策略。 慢性肾脏炎症被怀疑是难治性高血压的致病机制。的目标是 这项拨款计划是为了研究慢性炎症模型对控制肾脏炎症的作用。 疾病。系统性红斑狼疮(SLE)是一种慢性自身免疫性炎症，其中肾脏炎症 先于系统性红斑狼疮的高血压发展；因此，它是一个合适的疾病模型用于 阐明高血压炎症起源的机制。 内源性神经免疫调节系统，如新的胆碱能抗炎途径，参与其中 在正常控制下过度发炎。我们的数据表明，增强迷走神经对脾的传导 通过全身药理学途径减少肾脏炎症和血压 实验性系统性红斑狼疮小鼠模型。在此基础上，我们假设活跃的神经免疫通路保护 通过抑制肾脏炎症和防止继发性肾小球疾病的发展 高血压。在本提案的目标1中，我们将确定中枢刺激迷走神经是否 化学发生和药理学技术通过胆碱能抗肾小球蛋白减少肾脏炎症 炎症途径，对系统性红斑狼疮有降压作用。这一目标的研究将阐明涉及到的中央核 在调节肾脏炎症方面，如果不加以控制，可能会导致系统性红斑狼疮的高血压。在目标2中，我们将 确定是否通过阻断其结节来抑制胆碱能抗炎途径 神经传递加剧了系统性红斑狼疮高血压。这一目标的研究将确定关键的神经/外周 适当的神经免疫调节所必需的成分。在目标3中，我们将确定一种内在的肾脏抗- 炎症途径与以脾为中心的胆碱能抗炎途径平行发挥作用。研究项目： 这一目标将检测高血压患者肾脏免疫细胞中局部乙酰胆碱的抗炎潜力。 易感系统性红斑狼疮小鼠使用体外研究和创新的嗅探细胞技术。整体而言，拟议的研究将会 解释动态平衡神经免疫机制如何控制健康中的肾脏炎症，以及提供 控制高血压和其他慢性炎症性疾病的肾脏炎症的治疗选择。

PROJECT SUMMARY By 2025, an estimated 1.6 billion people around the world will be hypertensive. This estimate may be higher given recently modified guidelines for hypertension that are inclusive of millions of additional patients. What is concerning is that almost 20% of all hypertensive patients are resistant to current therapies. Better understanding of the underlying mechanisms involved in the pathogenesis of hypertension is required in order to identify new and effective therapeutic strategies. Chronic renal inflammation is suspected to be a causal mechanism of resistant hypertension. The objective of this grant proposal is to examine the the control of renal inflammation using a model of chronic inflammatory disease. Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory in which renal inflammation precedes the development of hypertension in SLE; therefore, it is an appropriate disease model to use to elucidate mechanisms involved in the inflammatory origins of hypertension. Endogenous neuro-immunoregulatory systems like the novel cholinergic anti-inflammatory pathway are involved in the normal control of excessive inflammation. Our data indicate that boosting this vagus nerve-to-spleen pathway via systemic pharmacological approaches reduces renal inflammation and blood pressure in an experimental mouse model of SLE. Based on this, we hypothesize that active neuroimmune pathways protect the kidney by suppressing renal inflammation and preventing the subsequent development of hypertension. In Aim 1 of this proposal, we will determine if central stimulation of the vagus nerve via both chemogenetic and pharmacological techniques reduces renal inflammation through the cholinergic anti- inflammatory pathway, and is antihypertensive in SLE. Studies in this aim will elucidate central nuclei involved in the regulation of renal inflammation that if left unchecked can result in hypertension in SLE. In Aim 2, we will determine whether inhibiting the cholinergic anti-inflammatory pathway by blocking its nodes of neurotransmission exacerbates SLE hypertension. Studies in this aim will determine critical neural/peripheral components necessary for proper neuroimmune regulation. In Aim 3, we will determine if an intrinsic renal anti- inflammatory pathway works in parallel with the spleen-centric cholinergic anti-inflammatory pathway. Studies in this aim will examine the anti-inflammatory potential of local acetylcholine in renal immune cells in hypertension- prone SLE mice using in vitro studies and innovative sniffer cell technoogy. Overall, the proposed studies will explain how homeostatic neuroimmune mechanisms control renal inflammation in health, as well as offer therapeutic options for controlling renal inflammation in hypertension and other chronic inflammatory diseases.