Renal mechanisms of hypertension in autoimmune disease

高血压的患病率在自身免疫性疾病患者中显著增加，而且还在增长。 有证据表明，原发性高血压与自身免疫相关的免疫学变化有关，包括 产生自身抗体(免疫球蛋白)。自身免疫性疾病的基本机制 高血压在普通人群和美国现役军人和退伍军人中的流行情况仍然很差 明白了。这一建议将直接促进我们对自身免疫过程中高血压的理解，从而 缩小知识差距，最终将导致高血压治疗的改善，不仅对美国。 退伍军人，也适用于原发性高血压患者。我们之前已经确定1)和 实验小鼠模型与包括高血压在内的人类系统性红斑狼疮非常相似，具有显著的统计学意义 肾免疫细胞浸润；2)系统性红斑狼疮小鼠肾血管功能和肾钠离子受损 作为高血压发生的潜在因素的处理；3)肾脏产生的活性氧 种类增加，普通抗氧化剂治疗可减轻系统性红斑狼疮小鼠的高血压； 免疫抑制和抗炎治疗可预防高血压的发展 系统性红斑狼疮与肾脏氧化应激降低有关；以及5)循环免疫球蛋白，一个关键的致病机制 在自身免疫性疾病中，直接导致系统性红斑狼疮小鼠高血压。这些加在一起， 研究有力地表明，免疫介导的肾脏氧化应激增加是一种基本的 自身免疫过程中高血压流行的机制。尽管有这些证据，令人惊讶的是几乎没有 了解肾脏中活性氧物种的细胞来源，或细胞内的 系统性红斑狼疮期间增加肾脏氧化应激的机制。在初步研究中，我们发现肾脏 系统性红斑狼疮小鼠的中性粒细胞增加，这些小鼠产生髓过氧化物酶的免疫球蛋白，并 与中性粒细胞胞外陷阱(NETs)相关的中性粒细胞氧化爆发所必需的酶 与人类自身免疫性疾病有病因学联系。此外，我们还鉴定了针对该抗体的抗体 线粒体抗原，并有初步数据表明，线粒体呼吸功能受损， 随着线粒体活性氧物种的产生增加。综上所述，这些数据表明 自身免疫介导的免疫球蛋白、中性粒细胞和线粒体功能障碍在发病机制中的中心作用 高血压。这项建议将研究网络和免疫球蛋白如何在细胞水平上导致线粒体 前馈机制的功能障碍。我们认为这种前馈机制是通过免疫球蛋白来传播的。 介导了FcγR的激活，并随后激活了NLRP3炎症体。基于我们的 初步的和已发表的数据，我们的中心假设是在SLE期间，Net启动线粒体损伤 在肾脏中，这会导致产生升高到线粒体抗原的免疫球蛋白。自身抗体结合到 肾组织中的FcγR激活NLRP3炎症体，进一步损害线粒体功能。这套 上调线粒体ROS生成的前馈机制，导致肾血管功能障碍和 钠重吸收增加，导致动脉压升高。使用临床上相关的实验 模拟人类系统性红斑狼疮的模型，这一假说将在以下特定目标中进行检验：(1)检验 假设在SLE期间，中性粒细胞是肾脏线粒体功能障碍和 对高血压的发生有机械性的贡献。(2)检验假设：在SLE期间， 循环免疫球蛋白通过FcγR介导的活化促进受损的线粒体功能 炎症小体，导致ROS的产生，肾功能受损和高血压。这些实验将 大大提高了我们对导致肾功能变化的潜在病理的理解 系统性红斑狼疮患者和普通人群的高血压。

The prevalence of hypertension is markedly increased in patients with autoimmune disorders, and growing evidence links primary hypertension to immunological changes associated with autoimmunity including the production of autoantibodies (IgG). The underlying mechanisms by which autoimmunity contributes to the prevalent hypertension in the general population and U.S. active duty military and veterans remains poorly understood. This proposal will directly advance our understanding of hypertension during autoimmunity, thus narrowing a knowledge gap that will ultimately lead to improved treatment of hypertension not only for U.S. military veterans, but also for patients with primary hypertension. We previously established that 1) an experimental mouse model closely mimics human SLE including the prevalent hypertension with significant renal immune cell infiltration; 2) mice with SLE have impaired renal vascular function and renal sodium handling as an underlying factor in development of hypertension; 3) renal production of reactive oxygen species is increased, and treatment with general antioxidants attenuates the hypertension in mice with SLE; 4) immunosuppressive and anti-inflammatory treatments protect against the development of hypertension during SLE in association with reduced renal oxidative stress; and 5) circulating IgG, a critical pathogenic mechanism of autoimmune diseases, directly contribute to the hypertension in mice with SLE. Taken together, these studies strongly suggest that immune mediated increases in renal oxidative stress is a fundamental mechanism leading to the prevalent hypertension during autoimmunity. Despite this evidence, surprisingly little is understood about the cellular sources of reactive oxygen species in the kidneys, or the intracellular mechanisms that increase renal oxidative stress during SLE. In a preliminary study, we show that renal neutrophils are increased in mice with SLE and that these same mice make IgG to myeloperoxidase, an enzyme essential for the neutrophil oxidative burst and associated with neutrophil extracellular traps (NETs) that are pathogenically linked to autoimmune disease in humans. In addition, we identified IgG raised against mitochondrial antigens, and have preliminary data showing that mitochondrial respiration is impaired, along with increased production of mitochondrial reactive oxygen species. Taken together, these data suggest a central role for IgG, neutrophils and mitochondrial dysfunction in the pathogenesis of autoimmune mediated hypertension. This proposal will examine how NETs and IgG act at the cellular level to cause mitochondrial dysfunction in a feed forward mechanism. We propose that this feed forward mechanism is propagated by IgG mediated activation of FcγR, and the subsequent activation of the NLRP3 inflammasome. Based on our preliminary and published data, our central hypothesis is that during SLE, NETs initiate mitochondrial damage in the kidney that leads to the production of IgG raised to mitochondrial antigens. The autoantibodies bind to FcγR in the kidney and activate the NLRP3 inflammasome, further impairing mitochondrial function. This sets up a feed forward mechanism of mitochondrial ROS generation that causes renal vascular dysfunction and increased sodium reabsorption resulting in increased arterial pressure. Using a clinically relevant experimental model that closely mimics human SLE, this hypothesis will be tested in the following specific aims (1) To test the hypothesis that during SLE neutrophils are important mediators of renal mitochondrial dysfunction and mechanistically contribute to the development of hypertension. (2) To test the hypothesis that during SLE, circulating IgG promotes impaired mitochondrial function through FcγR mediated activation of the inflammasome, leading to ROS generation, impaired renal function and hypertension. These experiments will significantly advance our understanding of the underlying pathology for changes in renal function that cause hypertension both for patients with SLE and for the general population.