Immune Mechanisms of Salt-Sensitive hypertension

盐敏感性高血压的免疫机制

• 批准号: 10613511
• 负责人: Annet Kirabo
• 金额: $ 57.96万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-04 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613511
• 关键词: Acute; Adoptive Transfer; Adult; Amiloride; Antigen Presentation; Antigen-Presenting Cells; Autologous; Binding; Blood Glucose; Blood Plasma Volume; Blood Pressure; Calcium; Cardiovascular Diseases; Cell physiology; Cells; Cessation of life; Cholesterol; Classification; Clinic; Consumption; Data; Dendritic Cells; Diagnosis; Diagnostic; Diagnostic tests; Dietary intake; Disease; Electrostatics; Essential Hypertension; Excretory function; Exposure to; Extracellular Fluid; Future; Glycosaminoglycans; Goals; Human; Immune; Immunodeficient Mouse; Immunologic Deficiency Syndromes; Immunology; In Vitro; Individual; Infiltration; Inflammation; Inpatients; Investigation; Kidney; Knockout Mice; Lipids; Magnetic Resonance Imaging; Measures; Mediating; Mus; Muscle; NADPH Oxidase; Organ; Participant; Pathogenesis; Patients; Persons; Phenotype; Play; Proliferating; Proteins; Proteomics; Protocols documentation; Pulse Pressure; Regulation; Research; Resistance; Risk Factors; Role; Sampling; Scientist; Sgk protein; Skin; Sodium; Sodium Chloride; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Tissues; Vascular Diseases; Water; absorption; adduct; bench to bedside; blood pressure elevation; cardiovascular risk factor; cost effective; cytokine; diagnostic tool; dietary; dietary excess; endothelial dysfunction; epithelial Na+ channel; experimental study; graft vs host disease; high body mass index; humanized mouse; hypertensive; immune activation; in vivo; insight; interstitial; kidney dysfunction; metabolomics; migration; monocyte; mortality; neoantigens; normotensive; oxidation; personalized diagnostics; personalized therapeutic; public health relevance; renal damage; response; salt intake; salt sensitive; salt sensitive hypertension; success; therapy development; trait; transcriptomics; translational study; western diet

Project Summary: Salt-sensitivity of blood pressure (SSBP) is an independent risk factor for cardiovascular mortality not only in hypertensive, but also in normotensive adults. The diagnosis for SSBP is not feasible in the clinic due to lack of a simple diagnostic test, making it difficult to investigate therapeutic strategies. Most research efforts to understand the mechanisms of SSBP have focused on renal regulation of sodium (Na+). However, salt retention or plasma volume expansion are not enhanced in salt sensitive (SS) versus salt resistant (SR) individuals. In addition, over 70% of extracellular fluid is interstitial and therefore not directly controlled by renal salt and water excretion. Thus, further research is needed to understand the extrarenal mechanisms contributing to SSBP. We recently found that Na+ enters monocyte-derived dendritic cells through the amiloride sensitive epithelial Na+ channel (ENaC) and activates the NADPH oxidase leading to formation of highly reactive products of lipid oxidation known as isolevuglandins (IsoLGs). IsoLGs adduct to self-proteins and act as neoantigens, which activate T cells to produce cytokines that promote Na+ retention and blood pressure (BP) elevation. Interestingly, analogous to SSBP, we found considerable variability in the response of human monocytes to in vitro exposure to elevated Na+ which correlated with known cardiovascular risk factors. It is not known if this variability in the responsiveness of monocytes to elevated Na+ happens in vivo and if it contributes to the SSBP. Recent studies found that Na+ accumulates in the interstitium electrostatically bound to glycosaminoglycans but can be mobilized. This is relevant to circulating monocytes as they enter and re-emerge from the interstitium with increased ability to present antigens. Our data indicate that monocytes from humans with high skin Na+ are activated and have increased IsoLGs. This R01 proposal presents an opportunity to study how immune activation and interstitial Na+ interact to impact SSBP in well phenotyped SS and SR individuals. We hypothesize that circulating monocytes transmigrate into regions of elevated Na+ including the skin, muscle and kidney, and are activated via IsoLG-adduct formation leading to SSBP. In Aim 1, we will employ an inpatient Weinberger protocol to classify participants as SS or SR and measure tissue Na+ using 23NaMRI to determine if tissue Na+ and monocyte activation contribute to SSBP. In Aim 2, we will adoptively transfer monocytes with T cells from SS and SR people into immunodeficient NSG-(KbDb)null (IA)null mice and determine if monocytes from humans with SSBP induce T cell activation, endothelial dysfunction, end-organ damage and SSBP in the humanized mice. These translational studies will advance the field and reveal more feasible and cost-effective diagnostic and therapeutic strategies for SSBP. Our exciting preliminary data indicating that changes in monocyte IsoLGs mirror changes in BP in response to salt provide promise for not only a simple diagnostic tool, but also mechanistic insight into the pathogenesis of SSBP. Alongside efforts to develop therapies for SSBP by focusing on the kidney, we propose that interstitial Na+ and monocyte activation via IsoLGs are important targets.

项目摘要： 血压的盐敏感性（SSBP）是心血管死亡率的独立危险因素，不仅在 高血压，但在正常的成年人中也是如此。由于缺乏，SSBP的诊断是不可行的 一个简单的诊断测试，使得很难研究治疗策略。大多数研究工作 了解SSBP的机制集中在钠（NA+）的肾脏调节上。但是，保留盐 在盐敏感（SS）和耐盐（SR）个体中，或血浆体积膨胀并未增强。在 此外，超过70％的细胞外液是间质的，因此不直接由肾脏盐和水控制 排泄。因此，需要进一步的研究来了解促成SSBP的肾外机制。 我们最近发现，Na+通过Amiloride敏感上皮Na+进入单核细胞衍生的树突状细胞 通道（ENAC）并激活NADPH氧化酶，导致形成高度反应性脂质的产物 氧化称为异氯甘糖（Isolevuglandins）（隔离）。隔离对自我蛋白质的加合物并充当新抗原，这是 激活T细胞以产生促进Na+固定和血压（BP）升高的细胞因子。有趣的是， 类似于SSBP，我们发现人单核细胞对体外暴露的反应有很大的差异 升高的Na+与已知的心血管危险因素相关。尚不知道这种可变性是否在 单核细胞对升高的Na+的反应性发生在体内，并且是否有助于SSBP。 最近的研究发现，Na+积累在静态静脉内与糖胺聚糖结合，但 可以动员。这与循环单核细胞进入并从间质重新出现时有关 提高抗原的能力。我们的数据表明，皮肤高Na+的人类的单核细胞为 激活并增加了隔离。该R01提案提供了研究免疫激活的机会 和间质Na+相互作用以影响表型的SS和SR个体中的SSBP。我们假设这一点 循环单核细胞转移到Na+升高区域，包括皮肤，肌肉和肾脏，是 通过隔离 - 成型形成激活，导致SSBP。在AIM 1中，我们将采用住院温度 将参与者分类为SS或SR，并使用23namri测量组织Na+，以确定组织Na+和 单核细胞激活有助于SSBP。在AIM 2中，我们将通过SS的T细胞传递单核细胞 和SR人员进入免疫缺陷的NSG-（KBDB）null（Ia）无效小鼠，并确定是否来自人类的单核细胞 SSBP在人源化的小鼠中诱导T细胞激活，内皮功能障碍，最终器官损伤和SSBP。 这些翻译研究将推进该领域，并揭示更可行和成本效益的诊断和 SSBP的治疗策略。我们令人兴奋的初步数据，表明单核细胞隔离的变化镜像 响应盐的BP的变化不仅为简单的诊断工具提供了希望，还为机械提供了希望 深入了解SSBP的发病机理。除了为SSBP开发疗法的努力外，专注于肾脏， 我们建议通过隔离的间隙Na+和单核细胞激活是重要的目标。