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

原发性高血压与免疫学变化有关，包括自身抗体的产生， 与高血压的自身免疫性基础一致先天性免疫反应也具有核心作用 然而，先天免疫对自身免疫的机制性贡献 相关的高血压尚未研究。这项提案将研究一种新的先天免疫前馈 系统性红斑狼疮（SLE）是一种 主要影响年轻妇女，从而大大推动该领域更好地了解 免疫介导的高血压我们先前表明，一个实验性的雌性小鼠模型的人类 SLE表现为肾血管功能和钠处理功能受损、肾氧化应激和高血压， 被抗氧化剂改善。尽管如此，人们对活性氧的细胞来源知之甚少 在SLE相关高血压期间驱动肾功能变化的细胞内途径。 先天性免疫应答在SLE期间引起组织损伤中具有重要作用。这项建议会 检验中心假设，即在SLE期间，存在一种前馈机制驱动肾功能的产生， ROS，导致肾血管功能受损和肾小管钠重吸收增加。这个周期涉及 增加细胞应激信号的NET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NLRP 3炎性体， 通过促进NET的进一步产生以诱导额外的细胞应激来延续该周期。这将受到考验 在三个目的中：（1）在SLE期间，NETs通过增加肾ROS促进高血压， 血管和肾小管功能。(2)在SLE期间，细胞应激蛋白（HMGB1）增加线粒体ROS 产生导致NLRP 3炎性小体活化和进一步通过TLR 4介导的NET产生 机制(3)将检查来自SLE男性和女性的大型数据队列（约32，000人）， 炎症、免疫疗法和血压的临床标志物之间的关系。该提案 使用广泛建立的SLE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，沿着国家人类临床数据库， 严格测试这些目标。

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.