Gut Metabolites, T cells, and Salt-Sensitive Hypertension

肠道代谢物、T 细胞和盐敏感性高血压

• 批准号: 10568068
• 负责人: David L. Mattson
• 金额: $ 55.89万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10568068
• 关键词: Address; Adoptive Transfer; Affect; Anesthesia procedures; Animal Experiments; Animal Model; Animals; Attenuated; Blood Pressure; CD4 Positive T Lymphocytes; Cardiovascular Diseases; Carnitine; Cells; Cerebrovascular Disorders; Clinical; Conscious; Consumption; Dahl Hypertensive Rats; Data; Development; Diet; Dietary Component; Dietary Proteins; Disease; Exhibits; Free Radicals; Gene Expression; Glomerular Filtration Rate; Grain; Health Benefit; Human; Hypertension; Immune; Immunity; Individual; Infiltration; Inflammation; Kidney; Kidney Diseases; Knowledge; Lead; Link; Mediating; Mediator; NADPH Oxidase; Organ; Patients; Phagocytes; Phenotype; Plant Proteins; Plasma; Play; Population; Production; Propionates; Proteins; Publishing; Rattus; Renal function; Resistant Hypertension; Risk Factors; Rodent Model; Role; Severity of illness; Sodium; Sodium Chloride; Source; T-Lymphocyte; Testing; Therapeutic; Vascular resistance; Work; blood pressure elevation; blood pressure reduction; cardiovascular risk factor; experimental study; feeding; gut microbiota; human disease; human model; hypertensive; hypertensives; immune activation; insight; kidney vascular structure; microbial; modifiable risk; mortality; novel; protein intake; renal damage; salt sensitive; salt sensitive hypertension

SUMMARY Hypertension is a primary modifiable risk factor for cardiovascular, cerebrovascular, and renal disease, and is the largest individual contributing factor to disease and mortality in the world. Salt-sensitive hypertensive individuals, who comprise 30-50% of the hypertensive population, have greater mortality than subjects with salt- resistant hypertension and exhibit renal end-organ damage. Immunity and inflammation are implicated in hypertension and renal damage in humans and experimental animal, but the mechanisms triggering immunity in hypertension are not understood. Dietary components other than salt can also play an important role in the development of cardiovascular disease and hypertension. Interestingly, an inverse relationship has been demonstrated between plant protein intake and blood pressure, ultimately associating health benefits with greater plant protein consumption. We recently discovered a novel link between dietary protein intake, immune- activation, and hypertension in the Dahl Salt-Sensitive (SS) rat, a rodent model of human disease. The experiments in this proposal will test the overarching hypothesis that free radical production from phagocytic NOX2 in infiltrating CD4+ T cells in the kidney of Dahl SS leads to an inappropriate elevation of renal vascular resistance (RVR), a reduction in glomerular filtration rate (GFR), the retention of sodium, and the further development of hypertension following high salt feeding. As a corollary to this hypothesis, we propose that the microbial metabolite carnitine, released by consumption of animal-based diets, upregulates NOX2 in T cells and amplifies salt-sensitive hypertension. In contrast, the metabolite propionate, released from consumption of grain- based diets, downregulates NOX2 and diminishes the full amplitude of salt-sensitive hypertension. The hypothesis will be addressed in two specific aims. Aim 1 will address the mechanisms whereby alterations in dietary protein source affect the release of metabolites from the gut microbiota and determine the influence of these metabolites on NOX2 in T cells and in the development of salt-sensitive hypertension. Aim 2 will address the role of phagocytic NOX2 in CD4+ T cells as a mediator of inappropriately increased renal vascular resistance and the development of salt-sensitive hypertension in Dahl SS by adoptive transfer of either wild type or NOX2- deficient CD4+ T cells into SS rats lacking T cells. This work will transform the understanding of salt-sensitive hypertension by utilizing novel animal models and approaches to demonstrate the mechanisms whereby dietary protein intake modifies immune mechanisms which serve to amplify disease severity. These studies should reveal new paradigms and provide insight with the potential to transform clinical/therapeutic approaches for the treatment of salt-sensitive hypertension.

概括 高血压是心血管，脑血管和肾脏疾病的主要可修改风险因素，是 最大的个人促成了世界上疾病和死亡率的因素。盐敏感高血压 占高血压人口的30-50％的个人比患有盐的受试者具有更大的死亡率 耐药性高血压和肾脏最终器官损伤。免疫和炎症与 人类和实验性动物的高血压和肾脏损害，但是机制引发了免疫力 高血压尚不清楚。盐以外的饮食成分也可以在 心血管疾病和高血压的发展。有趣的是，逆关系已经 在植物蛋白摄入和血压之间证明，最终将健康益处与 更大的植物蛋白消耗。我们最近发现了饮食蛋白摄入，免疫 - Dahl盐敏感（SS）大鼠的激活和高血压，这是人类疾病的啮齿动物模型。 该提案中的实验将检验总体假设，即从 DAHL SS肾脏中浸润CD4+ T细胞中的吞噬NOX2导致肾脏不当升高 血管耐药性（RVR），肾小球滤过率（GFR）的降低，钠的保留，进一步 高盐喂养后高血压的发展。作为这一假设的推论，我们建议 通过消费动物饮食而释放的微生物代谢产物肉碱，在T细胞中上调NOX2和 放大盐敏感的高血压。相比之下，丙酸代谢物是由于谷物的消费而释放的 基于饮食，下调NOX2并减少盐敏感高血压的全部振幅。这 假设将在两个具体目标中解决。 AIM 1将解决改变的机制 饮食蛋白质来源会影响肠道菌群中代谢产物的释放，并确定 这些代谢物在T细胞中的NOX2和盐敏感性高血压的发展中。 AIM 2将解决 吞噬NOX2在CD4+ T细胞中的作用是不适当增加肾血管抗性的介体 以及通过野生型或NOX2-的过继转移DAHL SS中盐敏感的高血压的发展 缺乏CD4+ T细胞进入缺乏T细胞的SS大鼠。这项工作将改变对盐敏感的理解 高血压通过利用新型动物模型和方法来证明饮食的机制 蛋白质摄入修饰可扩大疾病严重程度的免疫机制。这些研究应该 揭示新的范例，并提供有可能改变临床/治疗方法的见解 盐敏感高血压的治疗。