Innate Immune Mediated Changes in Renal Function to Cause Hypertension in Females with Autoimmune Disease

原发性高血压与免疫变化有关，包括自身抗体的产生，这些变化 与高血压的自身免疫基础相一致。先天免疫反应也起着核心作用。 在自身免疫的发展中；然而，天然免疫对自身免疫的机制贡献 相关的高血压尚未被研究过。这项提议将研究一种新的先天免疫前馈 系统性红斑狼疮(SLE)期间促进高血压的机制 主要影响年轻女性，从而显著推动该领域向更好地了解 免疫介导的高血压。我们之前展示了一种人类的实验雌性小鼠模型 系统性红斑狼疮表现为肾血管功能和钠处理受损，肾脏氧化应激和高血压 被抗氧化剂改善了。尽管如此，人们对活性氧的细胞来源知之甚少。 在系统性红斑狼疮相关高血压期间推动肾功能改变的种类或细胞内途径。 先天免疫反应在系统性红斑狼疮的组织损伤中起着重要作用。这项提议将 检验中央假设，即在SLE过程中，有一种前馈机制驱动肾脏的生成 ROS，导致肾血管功能受损和肾小管钠重吸收增加。这个循环涉及到 增加细胞应激信号的网络的存在，包括HMGB1，TLR4介导的线粒体 功能障碍和ROS的产生。线粒体ROS激活NLRP3炎症体， 通过促进下一代Net来诱导额外的细胞压力，从而使循环永久化。这将会被测试 在三个目标中(1)在SLE期间，Net通过增加肾脏ROS而促进高血压，从而导致肾脏受损 血管和肾小管功能。(2)在SLE过程中，细胞应激蛋白(HMGB1)增加线粒体ROS 通过TLR4介导的导致NLRP3炎症体激活和进一步净产生的生成 机制。(3)将对SLE男性和女性的大型数据队列(约32,000人)进行检查 炎症临床标记物、免疫治疗和血压之间的关系。这项建议 使用广泛建立的系统性红斑狼疮模型，创新的遗传模型，最先进的生理学， 药理学和免疫学方法，以及国家人类临床数据数据库，以 严格检验这些目标。

Primary hypertension is linked with immunological changes, including autoantibody production, that are consistent with autoimmune underpinnings of hypertension. The innate immune response also has a central role in the development of autoimmunity; however, the mechanistic contributions of innate immunity to autoimmune associated hypertension have not been studied. This proposal will examine a novel innate immune feedforward mechanism that promotes hypertension during systemic lupus erythematosus (SLE), a disorder that predominantly affects young women, thus significantly advancing the field towards a better understand of immune mediated hypertension. We previously showed that an experimental female mouse model of human SLE exhibits impaired renal vascular function and sodium handling, renal oxidative stress, and hypertension that is ameliorated by antioxidants. Despite this, little is understood about the cellular sources of reactive oxygen species or the intracellular pathways that drive changes in renal function during SLE associated hypertension. The innate immune response has an important role in causing tissue damage during SLE. This proposal will test the central hypothesis that during SLE there is a feedforward mechanism driving the generation of renal ROS, leading to impaired renal vascular function and increased tubular sodium reabsorption. This cycle involves the presence of NETs that increase cell stress signals, including HMGB1, TLR4 mediated mitochondrial dysfunction, and the production of ROS. Mitochondrial ROS activate the NLRP3 inflammasome, which perpetuates the cycle by promoting further generation of NETs to induce additional cell stress. This will be tested in three aims (1) During SLE, NETs promote hypertension by increasing renal ROS that causes impaired renal vascular and tubular function. (2) During SLE, cell stress proteins (HMGB1) increase mitochondrial ROS generation leading to NLRP3 inflammasome activation and further NET production through a TLR4 mediated mechanism. (3) A large data cohort (approximately 32,000) from men and women with SLE will be examined for relationships between clinical markers of inflammation, immunotherapies, and blood pressure. The proposal uses widely established models of SLE, an innovative genetic model, state-of-the-art physiological, pharmacological, and immunological methods, along with a national data base of human clinical data to rigorously test these aims.