Immune Mechanisms of Salt-Sensitive hypertension

盐敏感性高血压的免疫机制

• 批准号: 10401485
• 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/10401485
• 关键词: Acute; Adoptive Transfer; Adult; Amiloride; Antigen-Presenting Cells; Antigens; Autologous; Blood Glucose; Blood Plasma Volume; Blood Pressure; Calcium; Cardiovascular Diseases; Cell physiology; Cells; Cessation of life; Cholesterol; Clinic; Consumption; Data; Dendritic Cells; Diagnosis; Diagnostic; Diagnostic tests; Dietary intake; Electrostatics; Essential Hypertension; Excretory function; Exposure to; Extracellular Fluid; Future; Glycosaminoglycans; Goals; Human; Immune; Immunodeficient Mouse; Immunology; In Vitro; Individual; Infiltration; Inflammation; Inpatients; Investigation; Kidney; Knockout Mice; Lead; 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; adduct; base; 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; 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.

项目概要： 盐敏感性血压（SSBP）是心血管死亡的独立危险因素，不仅在 高血压，但也适用于血压正常的成年人。由于缺乏相关证据，SSBP 的诊断在临床上不可行。 简单的诊断测试，使得研究治疗策略变得困难。大多数研究工作 了解 SSBP 的机制主要集中在肾脏对钠 (Na+) 的调节。但盐潴留 与耐盐 (SR) 个体相比，盐敏感 (SS) 个体的血浆容量扩张并未增强。在 此外，超过 70% 的细胞外液是间质液，因此不受肾盐和水的直接控制 排泄。因此，需要进一步研究来了解导致 SSBP 的肾外机制。 我们最近发现Na+通过阿米洛利敏感的上皮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，导致形成高反应性脂质产物 氧化称为异黄酮素 (IsoLGs)。 IsoLG 与自身蛋白加合并充当新抗原， 激活 T 细胞产生细胞因子，促进 Na+ 潴留和血压 (BP) 升高。有趣的是， 与 SSBP 类似，我们发现人类单核细胞对体外暴露的反应存在相当大的差异 Na+ 升高与已知的心血管危险因素相关。目前尚不清楚这种变化是否 单核细胞对升高的 Na+ 的反应发生在体内，并且它是否有助于 SSBP。 最近的研究发现，Na+ 在间质中积聚，通过静电与糖胺聚糖结合，但 可以被动员起来。这与循环单核细胞进入间质并从间质重新出现时相关。 增强呈递抗原的能力。我们的数据表明，皮肤 Na+ 含量高的人类的单核细胞 激活并增加了 IsoLG。这个 R01 提案提供了一个研究免疫激活如何进行的机会 和间质 Na+ 相互作用，影响表型良好的 SS 和 SR 个体的 SSBP。我们假设 循环单核细胞迁移到 Na+ 升高的区域，包括皮肤、肌肉和肾脏，并且 通过 IsoLG 加合物形成激活，导致 SSBP。在目标 1 中，我们将采用住院患者温伯格方案 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 单核细胞活化有助于 SSBP。在目标 2 中，我们将通过 SS 的 T 细胞过继转移单核细胞 和 SR 人进入免疫缺陷 NSG-(KbDb)null (IA)null 小鼠，并确定来自人类的单核细胞是否具有 SSBP 在人源化小鼠中诱导 T 细胞活化、内皮功能障碍、终末器官损伤和 SSBP。 这些转化研究将推动该领域的发展，并揭示更可行且更具成本效益的诊断和治疗方法。 SSBP 的治疗策略。我们令人兴奋的初步数据表明单核细胞 IsoLG 的变化反映了 盐引起的血压变化不仅为简单的诊断工具提供了希望，而且还为机制提供了希望 深入了解 SSBP 的发病机制。除了通过关注肾脏来开发 SSBP 疗法之外， 我们认为通过 IsoLG 激活间质 Na+ 和单核细胞是重要的目标。