The Kidney, Hypertension, Pregnancy and Inflammation

描述(申请人提供)：免疫机制的慢性激活有助于先兆子痫和妊娠期高血压的病理生理学。先兆子痫妇女循环中的细胞因子、中性粒细胞和淋巴细胞升高，产生针对血管紧张素II I型受体(AT1-AA)的激动性自身抗体。然而，胎盘缺血和免疫激活与妊娠期高血压发病之间的确切联系尚不清楚。一个可能的机制是，导致AT1-AA的慢性炎症促进了氧化应激和内皮功能障碍，导致肾脏血流动力学改变，并通过增强与血管紧张素II和血管紧张素II 1型受体的相互作用而降低肾压钠尿。我们已经证明，妊娠大鼠子宫灌流压力降低(RUPP)是一种先兆子痫大鼠模型，是产生AT1-AA的重要刺激因素。此外，RUPP引起的高血压与炎症细胞因子、内皮素-1(ET-1)和活性氧(ROS)的升高以及肾脏血浆流量、GFR和肾脏排泄功能的减少有关。我们的初步数据表明，RUPP与淋巴细胞的升高有关，这些淋巴细胞的枯竭会钝化RUPP大鼠AT1-AA、ET-1的产生和高血压。此外，我们的初步数据支持这样的假设，即AT1-AA与AT1受体之间的相互作用，增强了肾微循环和血管对血管紧张素转换酶的敏感性。在这项建议中要检验的中心假设是，妊娠大鼠对胎盘缺血的高血压反应与T辅助细胞的激活有关，T辅助细胞反过来通过B淋巴细胞介导AT1-AA的产生。此外，我们认为AT1-AA和AngII通过AT1受体相互作用，促进ET-1和ROS的产生，导致妊娠期肾脏血流动力学下降和血压升高。为了验证这一假说，我们将使用一种综合的生理学方法，辅以分子、免疫学、体外细胞培养和体内技术，以解决以下三个特定目标：1)胎盘缺血反应中抑制CD4+T淋巴细胞调节机制是否会导致内源性AT1-AA介导的妊娠期高血压？2)验证效应分子CD4+辅助性T细胞/TH17介导的AT1-AA产生升高血压和降低肾血流动力学响应胎盘缺血的假说3)验证AT1-AA增强妊娠大鼠肾脏和血压对Ang II的敏感性的假说。

DESCRIPTION (provided by applicant): Chronic activation of immune mechanisms contributes to the pathophysiology of preeclampsia, hypertension during pregnancy. Preeclamptic women have elevated circulating cytokines, neutrophils and lymphocytes producing an agonistic autoantibody to the angiotensin II type I receptor (AT1-AA). However, the exact pathway linking placental ischemia and immune activation with the development of hypertension during pregnancy has yet to be clearly defined. One possible mechanism is that chronic inflammation resulting in the AT1-AA promotes oxidative stress and endothelial dysfunction leading to altered renal hemodynamics and reduced renal pressure natriuresis by enhanced interactions with Angiotensin II and the Angiotensin II type 1 receptor. We have shown that reduced uterine perfusion pressure (RUPP) in pregnant rats, a rat model of preeclampsia, is an important stimulus for the production of the AT1-AA. Moreover, hypertension produced by RUPP is associated with enhanced inflammatory cytokines, endothelin-1 (ET-1) and reactive oxygen species (ROS) and reductions in renal plasma flow, GFR, and renal excretory function. Our preliminary data indicate the RUPP is associated with elevated lymphocytes and that depletion of these lymphocytes blunts production of the AT1-AA, ET-1 and hypertension in RUPP rats. Furthermore, our preliminary data supports the hypothesis that interactions between AT1-AA with the AT1 receptor, enhances renal microcirculatory and vascular sensitivity to ANGII. The central hypothesis to be tested in this proposal is hypertension in response to placental ischemia in pregnant rats is associated with T helper cell activation which in turn mediate the production of AT1-AA via B lymphocytes. In addition, we propose that the AT1-AA and ANGII interact via the AT1 receptor to enhance the production of ET-1 and ROS leading to decreases in renal hemodynamics and increases in blood pressure during pregnancy. To test this hypothesis an integrative physiological approach complemented with molecular, immunological, in vitro cell culture and in vivo techniques will be used to address the following 3 specific aims: 1) Does inhibited CD4+T lymphocyte regulatory mechanism in response to placental ischemia lead to endogenous AT1-AA mediated hypertension during pregnancy?2) To test the hypothesis that effector CD4+Thelper/TH17 mediated AT1-AA production increases blood pressure and decreases renal hemodynamics in response to placental ischemia in pregnant rats 3) To test the hypothesis that AT1-AA enhances renal and blood pressure sensitivity to ANG II in pregnant rats.