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

项目摘要 在约7000万美国高血压患者中，近一半表现出盐敏感性， 在非裔美国人中比例更高。我们在Dahl盐敏感（SS）大鼠模型中的观察结果 血压升高、蛋白尿、T淋巴细胞和巨噬细胞浸润 盐敏感性高血压患者的肾脏然而，调解机制 高血压中免疫细胞浸润到肾脏并激活适应性免疫的情况尚不清楚。 NLRP 3炎性小体是一种新型的多蛋白复合物，在天然免疫系统中起着关键作用 启动，特别是在无菌炎症，并可能是先天和适应性之间的缺失环节 盐敏感性高血压的免疫机制目前的研究将测试一般假设， SS肾中NLRP 3炎性体的氧化还原活化介导适应性免疫的启动 反应和随后的T淋巴细胞浸润，放大盐诱导的高血压和肾 损害为了检验这一假设，提出了两个具体目标。AIM 1将测试假设， NLRP 3炎性体的表达和活化将在DahlSS大鼠肾脏中增加， 从低盐（LS，0.4%NaCl）饮食过渡到高盐（HS，4.0%NaCl）饮食，并测试药理学 抑制NLRP 3炎性体活化减轻Dahl盐诱导高血压和肾损伤 党卫军老鼠。为了了解氧化还原机制如何促进这一途径，AIM 2将测试以下假设： 活性氧（ROS）介导Dahl SS大鼠肾脏中的NLRP 3炎性体活化，并测试 来自肾实质的ROS相对于浸润免疫细胞对NLRP 3炎性体的贡献 通过全身照射/骨髓移植（TBI/BMT）研究激活。这一提议将是第一个 为了研究Dahl SS大鼠中NLRP 3炎性小体活化中ROS的产生， 这种新的先天性免疫机制，以盐诱导的适应性免疫应答的启动，渗透 T淋巴细胞进入肾脏，导致高血压和肾损伤的最终进展。 这些研究的完成将明确NLRP 3炎性小体的作用，并将使新的 在定义盐敏感性高血压中启动免疫系统级联反应的关键因素方面取得了突破。 这些发现将有可能为新疗法的开发做出巨大贡献。 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， 克服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.