The Kidney, Hypertension, Pregnancy and Inflammation

描述（由申请方提供）：免疫机制的慢性激活有助于先兆子痫、妊娠期高血压的病理生理学。先兆子痫的妇女有升高的循环细胞因子，中性粒细胞和淋巴细胞产生的激动性自身抗体的血管紧张素II I型受体（AT 1-AA）。然而，胎盘缺血和免疫激活与妊娠期高血压发展之间的确切途径尚未明确。一种可能的机制是导致AT 1-AA的慢性炎症促进氧化应激和内皮功能障碍，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，导致肾血流动力学改变和肾压尿钠排泄减少。我们已经表明，降低子宫灌注压（RUPP）在妊娠大鼠，大鼠模型先兆子痫，是一个重要的刺激生产的AT 1-AA。此外，RUPP产生的高血压与炎性细胞因子、内皮素-1（ET-1）和活性氧（ROS）的增强以及肾血浆流量、GFR和肾排泄功能的降低相关。我们的初步数据表明，RUPP与淋巴细胞升高有关，这些淋巴细胞的耗竭减弱了RUPP大鼠AT 1-AA、ET-1和高血压的产生。此外，我们的初步数据支持AT 1-AA与AT 1受体之间的相互作用增强肾微循环和血管对ANGII的敏感性的假设。在该提议中待检验的中心假设是妊娠大鼠中对胎盘缺血的高血压反应与T辅助细胞活化相关，T辅助细胞活化进而介导通过B淋巴细胞产生AT 1-AA。此外，我们提出AT 1-AA和ANGII通过AT 1受体相互作用，以增强ET-1和ROS的产生，导致妊娠期间肾血流动力学降低和血压升高。为了验证这一假设，将采用分子、免疫学、体外细胞培养和体内技术相结合的综合生理学方法来解决以下3个具体目标：1）胎盘缺血时受抑制的CD 4 +T淋巴细胞调节机制是否导致内源性AT 1-AA介导的妊娠期高血压？2)验证效应子CD 4 + Thlper/TH 17介导的AT 1-AA产生增加血压和降低妊娠大鼠对胎盘缺血的肾血流动力学的响应的假设3）验证AT 1-AA增强妊娠大鼠对ANG II的肾和血压敏感性的假设。

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.