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: 10563126
• 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/10563126
• 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; Health; Hepatic; Histologic; Human; Hypertension; Hypertrophy; Impaired Renal Function; Impairment; Intervention; Kidney; Kidney Diseases; Kidney Failure; Knowledge; Maternal Mortality; Measurement; Mentors; Mentorship; Modeling; Morbidity - disease rate; Mothers; Operative Surgical Procedures; Outcome; Oxidative Stress; Pathogenesis; 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 cell infiltration; T-Lymphocyte; Testing; Tissues; United States; Uterus; Woman; adverse pregnancy outcome; disease phenotype; endothelial dysfunction; fetal; hemodynamics; improved; indexing; kidney dysfunction; maternal morbidity; maternal outcome; mortality; neutrophil cytosol factor 67K; normotensive; novel; pharmacologic; renal damage; restoration

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 由T细胞产生的NOX 2衍生的氧化应激有助于母体发育 达尔盐敏感大鼠的综合症。先兆子痫（PE）是一种妊娠特异性疾病， 以妊娠20周后出现的高血压和蛋白尿（母体综合征）为特征。 PE是美国孕产妇发病率和死亡率的主要原因，影响约5-7%的 怀孕。此外，患有高血压或慢性肾脏疾病的女性， 发展PE的风险。随着美国PE率的上升， 该病的发病机制尚未确定。目前认为PE发病机制的概念 这是一个两步过程：1）胎盘形成不当和螺旋动脉重塑，2） 母亲综合征目前的动物模型需要手术或药物干预来开发 PE样表型;然而，这些模型不能研究疾病过程的第一步。 我们的初步数据表明，达尔盐敏感（SS）大鼠正是这样一种动物模型，以帮助 研究PE的机制，因为它在低盐（0.4%NaCl）下自发产生PE 饮食.目前的研究将检验中心假设，即Dahl SS大鼠的母体综合征是一种结果， 胎盘形成不当，导致T细胞浸润到肾脏和胎盘组织中， 释放活性氧（ROS），导致内皮功能障碍和发展 高血压和肾损害。为了检验这一假设，提出了三个具体目标。AIM 1将首先测试 假设T细胞来源的ROS（NOX 2来源的）在Dahl SS大鼠中引起母体综合征， 新的脾细胞转移方法。AIM 2将证明T细胞来源的ROS导致内皮细胞损伤。 在母体综合症中发展的功能障碍。有趣的是，这种母体综合征表型发生在一个 发散的方式与约50%的SS大鼠发育的母亲和另一半的保护。AIM 3将 研究PE期间发生的肾功能不全以及发生慢性肾脏病的风险增加 导致Dahl SS大鼠死亡率增加的疾病。这种母体综合征表型与 在临床环境中观察到的，这个模型提供了一个独特的机会来研究整个疾病 PE的过程。完成本提案中的研究将建立T细胞衍生的 ROS和内皮功能在PE中的作用，以更好地了解PE的潜在机制。