Nox2-derived oxidative stress produced by T cells contributes to the development of maternal syndrome in the Dahl salt-sensitive rat.

T 细胞产生的 Nox2 衍生氧化应激导致达尔盐敏感大鼠发生母体综合征。

• 批准号: 10370733
• 负责人: John H Dasinger
• 金额: $ 10.25万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-04 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10370733
• 关键词: Address; Advisory Committees; Affect; Animal Model; Aptitude; Arteries; Blood Urea Nitrogen; Cerebrum; Child; Chronic Kidney Failure; Clinical; Creatinine clearance measurement; Dahl Hypertensive Rats; Data; Development; Diet; Disease; Disease Progression; Economic Burden; Elderly; Endothelium; Ensure; Excretory function; Exhibits; Future; Genes; Genetic; Goals; Grant; Hepatic; Histologic; Human; Hypertension; Hypertrophy; Impaired Renal Function; Impairment; Intervention; Kidney; Kidney Diseases; Knowledge; Lead; Maternal Mortality; Measurement; Mentors; Mentorship; Modeling; Morbidity - disease rate; Mothers; Operative Surgical Procedures; Outcome; Oxidative Stress; Pathogenesis; Pharmacology; Phase; Phenotype; Placentation; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Principal Investigator; Process; Proteins; Proteinuria; Rattus; Reactive Oxygen Species; Resistance; Risk; Sodium Chloride; Spiral Artery of the Endometrium; Splenocyte; Syndrome; T-Lymphocyte; Testing; Tissues; Tumor-infiltrating immune cells; United States; Uterus; Woman; adverse pregnancy outcome; disease phenotype; endothelial dysfunction; fetal; health economics; hemodynamics; improved; indexing; kidney dysfunction; maternal morbidity; mortality; neutrophil cytosol factor 67K; normotensive; novel; renal damage; restoration; salt sensitive

Project Abstract NOX2-derived oxidative stress produced by T cells contributes to the development of maternal syndrome in the Dahl salt-sensitive rat. Preeclampsia (PE) is a pregnancy-specific disorder that is characterized by hypertension and proteinuria (maternal syndrome) developing after the 20th week of gestation. PE is the leading cause of maternal morbidity and mortality in the United States, affecting about 5-7% of pregnancies. Furthermore, women with preexisting hypertension or chronic kidney disease have an increased risk for developing PE. With rates of PE rising in the United States, the exact mechanism(s) responsible for the pathogenesis of the disease remain undetermined. The current notion of the pathogenesis of PE is thought to be a two-step process: 1) improper placentation and remodeling of the spiral arteries and 2) development of maternal syndrome. Current animal models require either a surgical or pharmacologic intervention to develop PE-like phenotypes; however, these models are not capable of investigating the first step in the disease process. Our preliminary data demonstrate that the Dahl salt-sensitive (SS) rat is just such an animal model to help investigate mechanisms of PE since it spontaneously develops PE while remaining on a low salt (0.4% NaCl) diet. The present studies will test the central hypothesis that maternal syndrome in Dahl SS rats is an outcome of improper placentation leading to the infiltration of T cells into kidney and placental tissues causing subsequent release of reactive oxygen species (ROS) that contributes to endothelial dysfunction and the development hypertension and renal damage. To test this hypothesis, three specific aims are proposed. AIM 1 will first test the hypothesis that T cell derived ROS (NOX2-derived) causes maternal syndrome in Dahl SS rats utilizing a novel splenocyte transfer approach. AIM 2 will demonstrate that T-cell derived ROS results in endothelial dysfunction that develops in maternal syndrome. Interestingly, this maternal syndrome phenotype occurs in a divergent fashion with about 50% of SS rats developing maternal and the other half are protected. AIM 3 will investigate the renal dysfunction that occurs during PE and the increased risk of developing chronic kidney disease leading to increased mortality in Dahl SS rats. This maternal syndrome phenotype is consistent with what is observed in clinical settings, and this model provides a unique opportunity to study the whole disease process of PE. Completion of the studies in this proposal will establish the interaction between T cell-derived ROS and endothelial function in PE to better understand the underlying mechanisms of PE.

项目摘要 T细胞产生的NOX2衍生的氧化应激有助于母亲的发展 达尔盐敏感大鼠中的综合征。子痫前期（PE）是一种妊娠特异性疾病 妊娠20周后发育的高血压和蛋白尿（母体综合征）的特征。 PE是美国孕产妇发病率和死亡率的主要原因，影响了约5-7％ 怀孕。此外，患有高血压或慢性肾脏疾病的女性有所增加 开发PE的风险。随着美国的pe率上升的速度，确切的机制负责 疾病的发病机理仍未确定。当前的PE发病机理的概念被认为是 成为一个两步的过程：1）螺旋动脉的胎盘不正确和重塑，2）开发 孕产妇综合征。当前的动物模型需要手术或药理干预才能发展 类似于PE的表型；但是，这些模型无法研究疾病过程中的第一步。 我们的初步数据表明，达尔盐敏感（SS）大鼠只是这样的动物模型 研究PE的机制，因为它自发发展PE，同时保持在低盐（0.4％NaCl）上 饮食。本研究将检验中心假设，即达尔SS大鼠中的母体综合征是结果 导致T细胞渗入肾脏和胎盘组织的不当胎盘不当 释放有助于内皮功能障碍和发育的活性氧（ROS） 高血压和肾脏损害。为了检验这一假设，提出了三个具体目标。 AIM 1将首先测试 T细胞得出的ROS（NOX2衍生）引起的假设导致了Dahl SS大鼠的母体综合征。 新型脾细胞转移方法。 AIM 2将证明T细胞派生的ROS导致内皮导致 孕产妇综合征发展的功能障碍。有趣的是，这种母体综合征表型发生在A 大约50％的SS大鼠发展产妇和另一半的不同时尚受到保护。目标3意志 调查PE期间发生的肾功能障碍，并增加患慢性肾脏的风险 疾病导致DAHL SS大鼠死亡率增加。这种母体综合征表型与 在临床环境中观察到的内容，该模型为研究整个疾病提供了独特的机会 PE的过程。该提案中的研究完成将建立T细胞衍生的相互作用 ROS和PE中的内皮功能更好地了解PE的基本机制。