NADPH oxidase-mediated NLRP3 Inflammasome Activation in Dahl Salt-Sensitive Hypertension

项目摘要 在约7000万患有高血压的美国人中，近一半的人表现出盐敏感， 在非裔美国人中，这一比例更高。Dahl盐敏感型(SS)大鼠模型的观察 与血压升高、蛋白尿、T淋巴细胞和巨噬细胞的浸润平行 进入肾脏，在盐敏感型人类高血压中观察到。然而，调解的机制 高血压时免疫细胞向肾脏的渗透和激活获得性免疫的机制尚不清楚。 NLRP3炎症体是一种新的多蛋白复合体，在先天免疫系统中发挥重要作用 启动，特别是在无菌炎症期间，可能是先天和适应性之间缺失的一环 盐敏感型高血压的免疫机制。目前的研究将检验这一普遍假设 SS肾脏NLRP3炎症体的氧化还原激活介导适应性免疫的启动 扩增盐诱导的高血压和肾脏的T淋巴细胞的反应和随后的渗透 损坏。为了验证这一假设，本文提出了两个具体目标。目标1将检验这一假设 Dahl SS大鼠肾脏NLRP3炎性小体表达和活化增加 从低盐(LS，0.4%氯化钠)饮食过渡到高盐(HS，4.0%氯化钠)饮食，并测试是否具有药理作用 抑制NLRP3炎性小体激活减轻盐诱导的高血压和肾损伤 SS大鼠。为了理解氧化还原机制如何对这一途径做出贡献，AIM 2将检验以下假设 活性氧(ROS)介导Dahl SS大鼠肾脏NLRP3炎性小体激活 肾实质ROS与免疫细胞在NLRP3炎症体中的作用 全身照射激活/骨髓移植(TBI/BMT)研究。这项提议将是第一个 Dahl SS大鼠NLRP3炎性小体激活过程中ROS产生的研究 这种新的先天免疫机制能够启动盐诱导的适应性免疫反应，渗透 T淋巴细胞进入肾脏，导致高血压和肾脏损伤的最终进展。 这些研究的完成将为NLRP3炎症小体确立明确的作用，并将使新的 在确定启动盐敏感型高血压免疫系统级联的关键因素方面取得突破。 这些发现将有可能对新疗法的开发做出重大贡献。 通过发现更精细的靶点、更早的干预策略和更有效的治疗方法， 这些研究有能力对大量人口产生积极影响，最终目标是有一天 战胜高血压和相关的心血管疾病。

Project Summary Nearly half of the ~70 million Americans with hypertension exhibit salt-sensitivity, with the prevalence disproportionately greater in African Americans. Our observations in the Dahl Salt-Sensitive (SS) rat model parallel the same elevation in blood pressure, albuminuria, and infiltration of T lymphocytes and macrophages into the kidney that is observed in salt-sensitive human hypertension. However, the mechanisms that mediate the infiltration of immune cells into the kidney and activate adaptive immunity in hypertension are unknown. The NLRP3 inflammasome is a novel multiprotein complex that plays a critical role in innate immune system initiation, especially during sterile inflammation, and may be the missing link between innate and adaptive immune mechanisms in salt-sensitive hypertension. The present studies will test the general hypothesis that redox activation of the NLRP3 inflammasome in the SS kidney mediates the initiation of the adaptive immune response and the subsequent infiltration of T lymphocytes that amplify salt-induced hypertension and renal damage. To test this hypothesis, two specific aims are proposed. AIM 1 will test the hypothesis that the expression and activation of the NLRP3 inflammasome will increase in Dahl SS rat kidneys during the transition from a low (LS, 0.4% NaCl) to high salt (HS, 4.0% NaCl) diet, and test whether pharmacological inhibition of NLRP3 inflammasome activation attenuates salt-induced hypertension and renal damage in Dahl SS rats. To understand how redox mechanisms contribute to this pathway, AIM 2 will test the hypothesis that reactive oxygen species (ROS) mediate NLRP3 inflammasome activation in Dahl SS rat kidneys, and test the contribution of ROS from the renal parenchyma versus infiltrating immune cells to NLRP3 inflammasome activation through total body irradiation/bone marrow transfer (TBI/BMT) studies. This proposal will be the first to study the production of ROS in the activation of NLRP3 inflammasomes in Dahl SS rats and the first to link this novel innate immune mechanism to salt-induced initiation of the adaptive immune response, the infiltration of T lymphocytes into the kidney, leading to the eventual progression of hypertension and renal injury. Completion of these studies will establish a clear role for the NLRP3 inflammasome and will make new breakthroughs in defining key factors that initiate the immune system cascade in salt-sensitive hypertension. These findings will have the potential to make big contributions in the development of new therapeutics. Through the discovery of more refined targets, earlier intervention strategies and more effective therapies, these studies have the power to positively impact a large population, with the ultimate goal of one day overcoming hypertension and related cardiovascular diseases.