Gut Metabolites, T cells, and Salt-Sensitive Hypertension

总结 高血压是心血管、脑血管和肾脏疾病的主要可改变的危险因素， 是世界上导致疾病和死亡的最大的个体因素。盐敏感性高血压 占高血压人群30-50%的个体的死亡率高于高盐受试者- 顽固性高血压并表现出肾终末器官损伤。免疫力和炎症与 高血压和肾损害的人和实验动物，但触发免疫的机制， 高血压不被理解。除盐以外的膳食成分也可以在 心血管疾病和高血压的发展。有趣的是， 植物蛋白摄入量和血压之间的关系，最终将健康益处与 更多的植物蛋白质消耗。我们最近发现了饮食蛋白质摄入，免疫- 激活，和高血压的达尔盐敏感（SS）大鼠，人类疾病的啮齿动物模型。 这项提案中的实验将检验一个总体假设，即自由基的产生来自于 在Dahl SS的肾脏中浸润的CD 4 + T细胞中的吞噬性NOX 2导致肾脏的不适当的升高。 血管阻力（RVR）、肾小球滤过率（GFR）降低、钠潴留和进一步的血管阻力增加。 高盐饮食后高血压的发展。作为这一假设的推论，我们提出， 微生物代谢物肉毒碱，通过食用动物性饮食释放，上调T细胞中的NOX 2， 放大了盐敏感性高血压相反，代谢产物丙酸盐，从谷物消费中释放出来， 基于饮食，下调NOX 2，并减少盐敏感性高血压的全部幅度。的 假设将在两个具体目标中得到解决。目标1将解决机制， 膳食蛋白质源影响代谢物从肠道微生物群的释放，并确定 这些代谢产物对T细胞中的NOX 2和盐敏感性高血压的发展起作用。目标2将解决 CD 4 + T细胞中的吞噬性NOX 2作为不适当增加的肾血管阻力的介质的作用 通过过继转移野生型或NOX 2- 将缺乏CD 4 + T细胞的SS大鼠转化为缺乏T细胞的SS大鼠。这项工作将改变对盐敏感性的理解， 通过利用新的动物模型和方法来证明饮食调节高血压的机制， 蛋白质的摄入改变了免疫机制，从而扩大了疾病的严重程度。这些研究应 揭示新的范式，并提供洞察力，有可能改变临床/治疗方法， 盐敏感性高血压的治疗。

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.