Renal mechanisms of hypertension in autoimmune disease

自身免疫性疾病中高血压的肾脏机制

• 批准号: 10436800
• 负责人: MICHAEL RYAN
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10436800
• 关键词: Affect; Anti-Inflammatory Agents; Antigens; Antioxidants; Attenuated; Autoantibodies; Autoimmune; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Binding; Blood Pressure; Blood Vessels; Cell surface; Cells; Clinical; Coupled; Data; Development; Disease; Endothelium; Enzymes; Essential Hypertension; Experimental Models; Funding; General Population; Generations; Health; Healthcare; Human; Hypertension; Immune; Immune system; Immunologics; Immunotherapy; Impaired Renal Function; Impairment; Infiltration; Inflammasome; Kidney; Knowledge; Lead; Link; Mediating; Mediator of activation protein; Methods; Military Personnel; Mitochondria; Mus; Myeloid Cells; Oxidative Stress; Pathogenicity; Pathology; Pathway interactions; Patients; Peroxidases; Pharmacological Treatment; Physiological; Plasma; Prevalence; Production; Publishing; Reactive Oxygen Species; Renal Hypertension; Renal function; Respiration; Respiratory Burst; Rheumatism; Role; Sodium; Source; Surface; Systemic Lupus Erythematosus; Testing; Therapeutic immunosuppression; Tubular formation; Vascular Diseases; Veterans; Woman; Work; active duty; autoimmune pathogenesis; autoimmune rheumatologic disease; base; blood pressure regulation; cell type; clinically relevant; experimental study; extracellular; hypertension treatment; improved; in vivo; innovation; insight; interstitial cell; kidney vascular structure; military veteran; military women; mitochondrial dysfunction; mouse model; neutrophil; pressure; receptor

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.

患有自身免疫性疾病的患者中高血压的患病率显着增加，而且患病率还在不断上升 有证据表明原发性高血压与自身免疫相关的免疫变化有关，包括 自身抗体（IgG）的产生。自身免疫导致的潜在机制 普通人群和美国现役军人和退伍军人的高血压患病率仍然很差 明白了。该提议将直接增进我们对自身免疫期间高血压的认识，从而 缩小知识差距，最终将改善高血压的治疗，不仅适用于美国 退伍军人，也适用于原发性高血压患者。我们之前确定 1) 实验小鼠模型密切模仿人类 SLE，包括普遍存在的高血压，具有显着的 肾脏免疫细胞浸润； 2）患有SLE的小鼠肾血管功能和肾钠受损 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，一般抗氧化剂治疗可减轻 SLE 小鼠的高血压； 4） 免疫抑制和抗炎治疗可预防高血压的发展 SLE 与肾脏氧化应激减少有关； 5) 循环 IgG，一种关键的致病机制 自身免疫性疾病的发生，直接导致 SLE 小鼠的高血压。综合起来，这些 研究强烈表明，免疫介导的肾脏氧化应激增加是一个根本原因。 自身免疫期间导致高血压流行的机制。尽管有这些证据，但令人惊讶的是， 了解肾脏中活性氧的细胞来源，或细胞内的活性氧 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 患有 SLE 的小鼠中性粒细胞增加，并且这些小鼠产生髓过氧化物酶 IgG，髓过氧化物酶是一种髓过氧化物酶。 中性粒细胞氧化爆发所必需的酶，并与中性粒细胞胞外陷阱 (NET) 相关 与人类自身免疫性疾病有致病性相关。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，同时 随着线粒体活性氧的产生增加。综合起来，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发病机制中的核心作用 高血压。该提案将研究 NET 和 IgG 如何在细胞水平上发挥作用，导致线粒体 前馈机制中的功能障碍。我们建议这种前馈机制是由 IgG 传播的 介导 FcγR 的激活，以及随后 NLRP3 炎性体的激活。基于我们的 根据初步和已发表的数据，我们的中心假设是，在 SLE 期间，NETs 引发线粒体损伤 肾脏中产生 IgG，产生线粒体抗原。自身抗体结合 肾脏中的 FcγR 并激活 NLRP3 炎性体，进一步损害线粒体功能。这一套 建立线粒体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。使用临床相关实验 密切模仿人类 SLE 的模型，该假设将在以下具体目标中进行测试 (1) 测试 假设 SLE 期间中性粒细胞是肾线粒体功能障碍的重要介质 机械地促进高血压的发展。 (2) 检验以下假设：在 SLE 期间， 循环 IgG 通过 FcγR 介导的线粒体功能激活促进线粒体功能受损 炎症小体，导致 ROS 生成、肾功能受损和高血压。这些实验将 显着增进了我们对导致肾功能变化的潜在病理学的理解 SLE 患者和一般人群的高血压。