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: 9339569
• 负责人: MICHAEL RYAN
• 金额: --
• 依托单位: G V SONNY MONTGOMERY VA MEDCIAL CENTER
• 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 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9339569
• 关键词: Adaptive Immune System; Address; Adverse effects; Affect; Age; Angiotensin II; Antibody Formation; Antibody-Producing Cells; Antigen-Antibody Complex; Attenuated; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; Biochemical; Biological Preservation; Blood Pressure; Blood Vessels; Bone Marrow; Cardiovascular system; Cell Communication; Cells; Chimera organism; Chronic; Clinical; Data; Development; Disease; Essential Hypertension; Family; Female; Filtration; Glomerular Filtration Rate; Glomerulonephritis; Health; Healthcare; Human; Hypertension; Immune; Immune system; Impairment; Inflammation; Inflammatory; Injury; Interleukin-17; Kidney; Knowledge; Mediating; Mediator of activation protein; Methods; Military Personnel; Modeling; Molecular; Mus; Natriuresis; Organ; Pathogenesis; Patients; Pharmaceutical Preparations; Physiological; Prevalence; Process; Production; Publishing; Renal Blood Flow; Reporting; Resistance; Rheumatism; Risk; Risk Factors; Role; Sodium; Structure; Systemic Lupus Erythematosus; T-Cell Depletion; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Testing; Th2 Cells; Therapeutic immunosuppression; Tissues; Tubular formation; Vascular resistance; Veterans; Woman; Work; autoreactive B cell; base; blood pressure reduction; blood pressure regulation; cardiovascular risk factor; clinical care; cytokine; hemodynamics; immune activation; improved; improved outcome; insight; interest; kidney vascular structure; mortality; mouse model; novel; patient population; pressure; prevent; public health relevance; response; salt sensitive hypertension; systemic autoimmune disease

 DESCRIPTION (provided by applicant): The prevalence of hypertension is markedly increased in women with systemic lupus erythematosus (SLE) for reasons that are not clear. Hypertension is an independent predictor of mortality and a major cardiovascular risk factor for this patient population. Renal injury and inflammation is common in patients with SLE which is significant to the risk of hypertension because of the kidney's central role in the long term blood pressure control. Growing evidence suggests that autoimmunity may underlie both human and experimental hypertension. Therefore, autoimmune induced renal inflammation may promote the development of hypertension in women with SLE. In support of this, preliminary data show that renal hemodynamic function is impaired in a hypertensive mouse model with SLE. In addition, our data show that hypertension in female SLE mice is mediated in part by B and T cells of the adaptive immune system. For example, the hypertension associates with autoantibody production and B cell depletion prevents the hypertension and renal injury. Renal and circulating levels of T cell associated cytokines (TNF-, IL-17) are increased in mice with SLE, as well. IL- 17 is widely implicated in autoimmune mediated tissue injury and renal TNF- promotes SLE associated hypertension. When T cells are depleted in SLE mice, autoantibodies are reduced and the progression of hypertension is attenuated. The lower blood pressure in T cell depleted SLE mice is associated with preservation of renal microvascular structure. The major focus of this proposal will be to determine the relative contribution of different immune cell subsets and their impact on renal hemodynamic function during SLE. The overall hypothesis is that the Th2 cell mediated B cell production of autoantibodies associated with SLE impairs renal hemodynamic function. In addition, Th1 and Th17 cells contribute to the hypertension by secreting cytokines (TNF- IL-17) that directly impair renal cortical or medullary vascular flow. The result of these changes is to shift the set point of the chronic pressure natriuresis relationship resulting in the development of hypertension. This specific aims will test whether (1) Th2/B cell interaction and the production of autoantibodies promotes the development of hypertension during SLE. (2) Th1 and Th17 cells contribute to the pathogenesis of hypertension and renal inflammation during SLE. (3) Adaptive immune system activation impairs renal hemodynamic function causing a hypertensive shift in the pressure natriuresis relationship during SLE. The proposed studies have significant clinical implications for veterans for whom hypertension remains a significant health concern. In addition, rheumatic diseases and their complications have been a major health concern for the U.S. military and their families for over 100 years. Therefore understanding mechanisms that promote SLE or its sequelae will improve the quality of clinical care for veterans with hypertension or SLE.

 描述（由申请人提供）： 患有系统性红斑狼疮 (SLE) 的女性的高血压患病率显着增加，其原因尚不清楚。高血压是死亡率的独立预测因素，也是该患者群体的主要心血管危险因素。肾损伤和炎症在患有系统性红斑狼疮的患者中很常见。由于肾脏在长期血压控制中发挥着核心作用，系统性红斑狼疮对高血压的风险具有重要意义。越来越多的证据表明，自身免疫可能是人类和实验性高血压的基础，因此，自身免疫引起的肾脏炎症可能会促进高血压的发展。为了支持这一点，初步数据表明，患有 SLE 的高血压小鼠模型的肾血流动力学功能受损。此外，我们的数据表明，雌性 SLE 小鼠的高血压部分是由 B 细胞和 T 细胞介导的。例如，高血压与自身抗体产生相关，B 细胞耗竭可预防 SLE 小鼠的肾和循环 T 细胞相关细胞因子（TNF-、IL-17）水平升高。 IL-17 广泛参与自身免疫介导的组织损伤，并且肾 TNF-α 会促进 SLE 相关的高血压。 SLE 小鼠与肾微血管结构的保存有关，该提案的主要重点是确定不同免疫细胞亚群的相对贡献及其对 SLE 期间肾血流动力学功能的影响。假设认为，Th2 细胞介导的 B 细胞产生与 SLE 相关的自身抗体会损害肾血流动力学功能。此外，Th1 和 Th17 细胞通过分泌细胞因子 (TNF-IL-17) 直接损害肾皮质或髓质血管血流，从而导致高血压。这些变化的结果是改变慢性压力排钠关系的设定点，从而导致高血压的发展。这一具体目标将测试是否（1）。 Th2/B 细胞相互作用和自身抗体的产生促进 SLE 期间高血压的发生 (2) Th1 和 Th17 细胞有助于 SLE 期间高血压和肾脏炎症的发病机制 (3) 适应性免疫系统激活损害肾脏血流动力学功能。 SLE期间压力尿钠关系的高血压转变对于退伍军人来说具有重要的临床意义，对于他们来说，高血压仍然是一个重要的健康问题。因此，了解促进 SLE 或其后遗症的机制将提高患有高血压或 SLE 的退伍军人的临床护理质量。