Immune Cells and Hypertension

项目3项目总结 本项目的目标是了解盐敏感型高血压的发病机制。盐诱导 喂食高盐饮食的Dahl盐敏感(SS)大鼠的高血压和肾脏损伤分两个阶段进行。一个 最初，不依赖于炎症的原发性血压(BP)升高之后是更多的 继发性血压显著升高，并伴有免疫细胞向肾脏的渗透增加 并最终发展为“恶性高血压”。降低肾脏免疫力的药理学和遗传学方法 细胞浸润减轻了盐诱导的高血压和SS大鼠肾脏损伤的这一次级阶段。这些 观察与高血压患者的数据平行，并表明免疫细胞在肾脏中发挥作用 通过放大疾病过程，在高血压的病理中发挥关键作用，但导致高血压的机制 免疫细胞在肾脏中的渗透和激活是未知的，也是本研究的重点。 求婚。在目前的方案中，我们提出了有趣的数据，表明肾脏血流灌注的初始升高 压力(RPP)引起分子级联反应，包括增加的H_2O_2，增加的mTORC_1，和激活 NLRP3炎症体。此外，我们的数据表明，过氧化氢和mTORC1可以激活炎性小体 介导免疫细胞向肾脏的渗透。基于这些数据，我们假设恶性 SS大鼠的高血压和肾损害是由RPP的原发升高引发的，这导致了 肾脏氧化应激(来自NOX4的H_2O_2)和mTORC1的相关增加。H_2O_2和mTORC_1变化 激活NLRP3炎症体，它介导先天和获得性免疫机制。由此产生的 渗透的免疫细胞然后在正反馈循环中从NOX2释放额外的过氧化氢，从而进一步 增强高血压和肾脏损害。这一假设将在三个具体目标中得到检验：目标1将检验 假设NLRP3炎症体受增加的过氧化氢和增加的mTORC1刺激，介导 SS在钠摄入量增加后的先天和获得性免疫反应，并导致 活化的T淋巴细胞渗入肾脏放大盐敏感型高血压和肾脏 损坏。目的2将验证以下假设：肾脏灌流压升高会增加肾内过氧化氢和 MTORC_1刺激SS大鼠肾脏NLRP3炎性小体和T细胞的浸润 高盐。目的3将验证T细胞渗入肾脏增强过氧化氢产生和 炎症小体激活，通过降低GFR和增加钠重吸收来放大高血压 进一步改变高血压性钠尿症，导致恶性高血压。这项提案旨在解决 重大健康问题，在概念和技术上都是创新的，利用了一套独特的实验 方法，并高度依赖项目1和项目1中其他调查员提供的专门知识。 2和这个PPG的核心A、B和C。

PROJECT 3 PROJECT SUMMARY The goal of the work in this Project is to understand the mechanisms of salt-sensitive hypertension. Salt-induced hypertension and renal injury in Dahl Salt-Sensitive (SS) rats fed a high salt diet proceeds in two phases. An initial, primary rise of blood pressure (BP), which is not dependent upon inflammation, is followed by a more dramatic, secondary rise of BP which is accompanied by increased infiltration of immune cells into the kidney and culminates in `malignant hypertension'. Pharmacological and genetic approaches that reduce renal immune cell infiltration attenuate this secondary phase of salt-induced hypertension and renal injury in SS rats. These observations parallel data obtained from hypertensive patients and indicate that immune cells in the kidney play a key role in the pathology of hypertension by amplifying the disease process, but the mechanisms leading to the infiltration and activation of immune cells in the kidney are unknown and are the focus of this research proposal. In the present proposal, we present intriguing data indicating that an initial elevation of renal perfusion pressure (RPP) elicits a molecular cascade involving increased H2O2, increased mTORC1, and activation of the NLRP3 inflammasome. Moreover, our data indicate that H2O2 and mTORC1 can activate the inflammasome which mediates infiltration of immune cells into the kidney. Based on these data, we hypothesize that malignant hypertension and renal damage in SS rats is triggered by a primary elevation of RPP which leads to an associated increase of renal oxidative stress (H2O2 from Nox4) and mTORC1. The altered H2O2 and mTORC1 activate the NLRP3 inflammasome which mediates innate and adaptive immune mechanisms. The resulting infiltrating immune cells then release additional H2O2 from Nox2 in a positive feedback cycle that further enhances hypertension and renal damage. This hypothesis will be tested in three Specific Aims: Aim 1 will test the hypothesis that the NLRP3 inflammasome, stimulated by increased H2O2 and increased mTORC1, mediates innate and adaptive immune responses in the SS following an elevation of sodium intake and results in the infiltration of activated T-lymphocytes into the kidney which amplify salt-sensitive hypertension and renal damage. Aim 2 will test the hypothesis that elevated renal perfusion pressure increases intrarenal H2O2 and mTORC1 which serve to stimulate the NLRP3 inflammasome and T-cell infiltration in the SS kidney when fed high salt. Aim 3 will test the hypothesis that T-cell infiltration into the kidney enhances H2O2 production and inflammasome activation which amplifies hypertension by decreasing GFR and increasing sodium reabsorption to further alter pressure natriuresis resulting in malignant hypertension. This proposal, which is addressing a significant health problem, is conceptually and technically innovative, utilizes a set of unique experimental approaches, and is highly dependent upon the expertise provided by the other investigators in Projects 1 and 2 and Cores A, B, and C of this PPG.