High salt diet potentiation of AngII HTN : Novel role for Th17 cell infiltration into the PVN

高盐饮食增强 AngII HTN：Th17 细胞浸润 PVN 的新作用

• 批准号: 9544380
• 负责人: Christopher Joseph Martyniuk
• 金额: $ 37.01万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9544380
• 关键词: Acute; Adoptive Transfer; Adrenergic Receptor; Alzheimer' s Disease; Angiotensin II; Angiotensin Type 1a Receptor; Animals; Antihypertensive Agents; Autoimmune Diseases; Autoimmune Process; Automobile Driving; Blood Pressure; Blood Vessels; Bone Marrow; Brain region; CD4 Positive T Lymphocytes; Cardiovascular Diseases; Cardiovascular system; Cells; Chemosensitization; Chronic; Colitis; Comorbidity; Data; Dementia; Development; Diabetes Mellitus; Diet; Disease; Down-Regulation; Employee Strikes; Enzymes; Event; Future; Genes; Genetic Transcription; Health; Helper-Inducer T-Lymphocyte; Hydrogen Peroxide; Hyperactive behavior; Hypertension; Hypothalamic structure; Immune; Immune Cell Activation; Immune System Diseases; Immune response; Immune system; Immunization; Infiltration; Inflammation; Inflammatory; Injection of therapeutic agent; Interleukins; Investigation; Kidney Diseases; Knowledge; Lead; Link; Losartan; Mediating; Microglia; Modeling; Molecular; Mus; Mutant Strains Mice; NF-kappa B; Nerve; Neurons; Nitric Oxide Synthase Type I; Nucleic Acid Regulatory Sequences; Obstructive Sleep Apnea; Outcome; Pathogenicity; Patients; Peripheral; Phenotype; Prevention therapy; Process; Property; Psoriatic Arthritis; Public Health; Refractory; Renin-Angiotensin System; Reporting; Research; Resistance; Resistant Hypertension; Risk Factors; Role; SOD2 gene; Signal Transduction; Sodium Chloride; Stroke; Subfornical Organ; Sum; Symptoms; Systemic Lupus Erythematosus; TNF gene; Tissues; Translating; Vasomotor; Viral; Viral Vector; Western Blotting; Work; base; cardiovascular risk factor; clinical development; cytokine; dietary salt; high salt diet; insight; molecular marker; mutant; nervous system disorder; neurogenic hypertension; neuroinflammation; novel; novel therapeutics; paraventricular nucleus; prevent; relating to nervous system; response; salt intake; salt sensitive; salt sensitive hypertension; transcription factor; vasoconstriction

Abstract Hypertension (HTN) is a prevalent cardiovascular condition and a leading risk factor for other cardiovascular diseases. Despite advances in prevention and therapy, ~20% of patients are resistant or refractory to current treatments. In most cases, treatment-resistant HTN (HTN) is strongly `neurogenic', being accompanied by exaggerated sympathetic nerve activity (SNA) and linked with renin-angiotensin system (RAS) and immune system activation. If it remains untreated, neurogenic hypertension can lead to numerous comorbidities such as stroke, dementia, diabetes, kidney disease, obstructive sleep apnea, and neurological disorders such as Alzheimer's disease. While studies of neurogenic HTN report inflammation in brain regions that control SNA, specific mechanisms driving hyperactivity of pre-sympathetic neurons have not been identified. Salt-sensitive HTN has been characterized by significant changes in neuronal properties following increased dietary salt intake and, most importantly, prior to blood pressure increase. Our recent work indicates that peripheral and central inflammatory mechanisms lead to molecular alterations in neurons in key autonomic brain regions such as the hypothalamus. More specifically, we found that moderately high salt diet (2%) activates bone marrow (BM)-derived IL17a-expressing CD4+ immune cells (ICs), which alone are capable of increasing blood pressure (BP). This was associated with infiltration of CD4+ ICs and activation of microglia in the paraventricular nucleus (PVN) of the hypothalamus, as well as with specific molecular changes in the PVN that may act as potent sensitizers of sympathetic control neurons, long implicated as drivers of exaggerated SNA in salt-sensitive HTN when challenged by angiotensin II (Ang II). Thus, this model provides several conceptual advantages in elucidation of early mechanisms of neuroinflammation-dependent neurogenic HTN, as we are able to investigate early mechanisms of neuronal changes prior to development of HTN. Our novel hypothesis is focused on the establishment of connection between infiltration of salt-activated IL17a-expressing ICs and exaggerated discharge of PVN pre-sympathetic neurons to Ang II. We postulate that the immune-driven adaptations strongly reflect transcriptional activity driven by nuclear factor kappa B (NF-kB), a major transcriptional factor activated by pro-inflammatory cytokines, including the IL-17a and microglial-derived TNFα. This results in the increase of SNA and promotes establishment of HTN not only through neurogenic vasoconstriction but also by stimulating continued release of BM ICs mediated by β1/β2 adrenoceptor activation in the BM. Outcomes will inform the future development of novel therapeutics to better manage neurogenic HTN, and potentially will extend to advance the treatment of other salt-exacerbated autoimmune disorders such as colitis, psoriatic arthritis and systemic lupus erythematosus.

抽象的 高血压（HTN）是一种普遍的心血管疾病，是其他心血管的领先危险因素 疾病。尽管预防和治疗方面取得了进步，但约有20％的患者对电流具有抵抗力或难治性 治疗。在大多数情况下，耐药的HTN（HTN）是强烈的“神经源”，是由 夸张的交感神经活动（SNA），与肾素 - 血管紧张素系统（RAS）和免疫联系 系统激活。如果不加以治疗，神经源性高血压会导致许多合并症 作为中风，痴呆症，糖尿病，肾脏疾病，阻塞性睡眠呼吸呼吸暂停和神经系统疾病，例如 阿尔茨海默氏病。神经源HTN的研究报告了控制SNA的大脑区域的炎症，但 尚未鉴定出促进同情神经元的过度活跃性的特定机制。盐敏感 HTN的特征是饮食盐增加后神经元特性的显着变化 摄入量，最重要的是，在血压升高之前。我们最近的工作表明外围和 中心炎症机制导致关键自主脑区域神经元的分子改变此类 作为下丘脑。更具体地说，我们发现中等高的盐饮食（2％）激活骨髓 （BM）衍生的表达IL17A的CD4+免疫细胞（ICS），仅能够增加血液 压力（BP）。这与CD4+ IC的浸润以及小胶质细胞的激活有关 下丘脑的副核（PVN），以及PVN中的特定分子变化 可能充当交感控制神经元的潜在传感器，长期以来被认为是夸张的SNA的驱动因素 当血管紧张素II挑战盐敏感HTN（ANG II）时。那，该模型提供了几种概念 阐明神经炎症依赖性神经源HTN的早期机制的优势，因为我们是 我们可以在HTN发展之前研究神经元变化的早期机制。我们的新假设 专注于建立盐激活IL17A表达IC和 夸张的PVN PVN交感神经元对ANG II的排放。我们假设免疫驱动 适应强烈反映由核因子Kappa B（NF-KB）驱动的转录活性，这是一个主要 促炎细胞因子激活的转录因子，包括IL-17A和小胶质细胞来源 TNFα。这导致SNA增加并促进HTN的建立，不仅是通过神经源 血管收缩，也是通过刺激由β1/β2肾上腺素受体介导的继续释放的BM IC BM激活。成果将为未来的新疗法开发，以更好地管理 神经源性HTN，并有可能延长以提高其他盐均质自身免疫的治疗 结肠炎，银屑病关节炎和全身性红斑狼疮等疾病。