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

项目摘要 T细胞产生的NOX2产生的氧化应激参与母体发育 Dahl盐敏感大鼠的综合征。子痫前期(PE)是一种妊娠特有的疾病， 以妊娠20周后出现高血压和蛋白尿(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，约5%-7%的人受到影响 怀孕。此外，既往有高血压或慢性肾脏疾病的女性 发展私募股权投资的风险。随着美国私募股权比率的上升，负责的确切机制(S) 该病的发病机制尚不清楚。目前关于PE发病机制的概念被认为是 这是一个分两步走的过程：1)螺旋动脉胎盘和重塑不当；2)发生 母性综合症。目前的动物模型需要外科手术或药物干预才能发展。 类似PE的表型；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，Dahl盐敏感(SS)大鼠就是这样一个帮助 研究PE在低盐(0.4%氯化钠)条件下自发形成PE的机制 节食。目前的研究将检验这一中心假设，即Dahl SS大鼠的母体综合征是一种结果 胎盘位置不当导致T细胞渗入肾脏和胎盘组织，从而导致 导致血管内皮细胞功能障碍的ROS释放及其发生发展 高血压和肾脏损伤。为了验证这一假设，本文提出了三个具体目标。Aim 1将首先测试 T细胞衍生的ROS(NOX2衍生)导致Dahl SS大鼠母体综合征的假说 新的脾细胞移植方法。目标2将证明T细胞来源的ROS导致内皮细胞 在母体综合征中发展的功能障碍。有趣的是，这种母体综合征表型发生在 分化的方式，大约50%的SS大鼠发育为母体，另一半受到保护。目标3将 研究PE期间发生的肾功能障碍和发展为慢性肾脏的风险增加 疾病导致Dahl SS大鼠死亡率增加。这一产妇综合征的表型与 在临床环境中观察到了什么，这个模型提供了一个研究整个疾病的独特机会 体育教学的过程。完成这项建议中的研究将建立T细胞来源的相互作用 ROS和内皮功能在PE中的作用，以更好地了解PE的潜在机制。

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.