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明显增加， 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， 产生自身抗体（IgG）。自身免疫促进免疫性疾病发生的潜在机制 在普通人群和美国现役军人和退伍军人中， 明白这一建议将直接推进我们对自身免疫性高血压的理解， 缩小知识差距，这将最终导致改善高血压的治疗，不仅对美国， 退伍军人，也适用于原发性高血压患者。我们以前建立了1）一个 实验小鼠模型非常类似于人类SLE，包括具有显著的高血压， 肾脏免疫细胞浸润; 2）SLE小鼠肾血管功能受损，肾钠 处理作为高血压发展的潜在因素; 3）肾脏产生活性氧 物种增加，并且用一般抗氧化剂治疗减轻患有SLE的小鼠的高血压; 4） 免疫抑制和抗炎治疗可以防止高血压的发展， SLE与肾脏氧化应激减少有关; 5）循环IgG，一种重要的致病机制 自身免疫性疾病，直接导致SLE小鼠高血压。综上所述各项 研究强烈表明，免疫介导的肾氧化应激增加是一种基本的 导致自身免疫性高血压流行的机制。尽管有这些证据， 了解肾脏中活性氧的细胞来源，或细胞内 在SLE期间增加肾脏氧化应激的机制。在一项初步研究中，我们表明，肾 中性粒细胞在SLE小鼠中增加，这些小鼠产生抗髓过氧化物酶的IgG， 中性粒细胞氧化爆发所必需的酶，与中性粒细胞胞外陷阱（NET）有关 与人类自身免疫性疾病有关的病原体。此外，我们还鉴定了针对 线粒体抗原，并有初步数据显示线粒体呼吸受损，沿着 线粒体活性氧的产生增加。这些数据表明， IgG、中性粒细胞和线粒体功能障碍在自身免疫介导的 高血压这项提案将研究如何NET和IgG在细胞水平上的行为，造成线粒体 前馈机制中的功能障碍。我们认为这种前馈机制是由IgG传播的， 介导的FcγR活化，以及随后的NLRP 3炎性体活化。基于我们 根据初步和已发表的数据，我们的中心假设是在SLE期间，NETs启动线粒体损伤， 在肾脏中，导致产生IgG，产生线粒体抗原。自身抗体结合到 FcγR在肾脏中的表达并激活NLRP 3炎性体，进一步损害线粒体功能。这设置 线粒体ROS产生的前馈机制导致肾血管功能障碍， 钠重吸收增加，导致动脉压升高。使用临床相关的实验 模型，密切模仿人类系统性红斑狼疮，这一假设将在以下具体目标进行测试（1）测试 在SLE期间中性粒细胞是肾线粒体功能障碍的重要介质的假设， 机械地促进高血压的发展。(2)为了验证在系统性红斑狼疮期间， 循环IgG通过FcγR介导的线粒体功能的激活促进受损的线粒体功能， 炎症小体，导致ROS产生，肾功能受损和高血压。这些实验将 显著推进我们对导致肾功能改变的潜在病理学的理解， SLE患者和一般人群的高血压。

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.