Hypertension, Kidney and Pregnancy

描述（由申请人提供）：在美国，妊娠性高血压或子痫前期（PE）估计影响5-7%的妊娠，尽管它是孕产妇死亡的主要原因，也是孕产妇和围产期发病率的主要因素，但没有有效的药物治疗来预防PE。目前，唯一有效的治疗PE的方法是早期分娩。根据最近的研究和本应用程序提供的初步数据，我们提出诱导应激反应基因血红素加氧酶-1 （HO-1）及其催化产物一氧化碳（CO）和胆红素可能为PE的治疗提供一种新的治疗方法。越来越多的证据表明，HO-1和/或其催化产物在胎盘缺血反应中对细胞损伤具有细胞保护作用，这是PE病理生理学中的一个重要启动事件。事实上，TNF1介导的胎盘绒毛外植体细胞损伤可以通过上调HO活性来预防。在一些体外模型中，HO通路也被证明可以抑制抗血管生成因子sFlt-1的释放。我们的初步数据还表明，在两种已建立的PE大鼠模型中，长期服用HO-1酶诱导剂或CO释放分子可显著减轻高血压。基于我们的初步数据，我们提出验证HO-1及其代谢产物CO和胆红素通过抑制sflt -1的产生来降低妊娠大鼠胎盘缺血时的血压和肾脏反应的中心假设。此外，我们提出HO-1衍生产品通过抑制胎盘中TNF1和活性氧（ROS）的生成，以及减弱TNF1和AT1受体自身抗体诱导的内皮细胞内皮素（ET-1）生成的增加，改善肾功能，降低总外周阻力和血压。为了验证这一假设，我们将在子宫灌注压（RUPP）长期降低引起的PE大鼠意识模型中检测动脉压、肾功能和内皮因子。除RUPP模型外，还将使用PE的sFlt-1模型来确定HO-1代谢物与sFlt-1、ET-1和ROS产生之间的相互作用，而体外胎盘外植体和内皮细胞培养模型将用于检测ho -代谢物在缺氧介导的TNF、ROS和胎盘sFlt-1和TNF诱导的ET-1产生中的直接相互作用。具体目标是：1)验证HO-1及其代谢物CO和胆红素可减弱妊娠大鼠对胎盘缺血的血压、肾脏和sFlt-1反应的假说2)验证HO-1及其代谢物CO和胆红素可减弱胎盘缺血和/或缺氧诱导的活性氧和TNF1升高的假说3)验证HO-1及其代谢物CO和胆红素可减弱胎盘缺血和/或缺氧诱导的TNF1升高的假说降低TNF1和AT1受体自身抗体诱导ET-1产生增加4)验证内源性HO-1通路在正常妊娠期间调节肾功能和动脉压及胎盘缺血反应中的作用

DESCRIPTION (provided by applicant): Pregnancy-induced hypertension or preeclampsia (PE) is estimated to affect 5-7% of all pregnancies in the U.S. Despite its position as a leading cause of maternal death and major contributor to maternal and perinatal morbidity, there is no effective drug treatment to prevent PE. At present, the only effective treatment for PE is early delivery. Based on recent studies and on preliminary data presented in this application, we propose that induction of the stress response gene, hemeoxygenase-1 (HO-1), and its catalytic products, carbon monoxide (CO) and bilirubin, may provide a novel therapeutic approach for the treatment of PE. There is mounting evidence that HO-1 and/or its catalytic products confer cytoprotection against cellular injury in response to placental ischemia, an important initiating event in the pathophysiology of PE. In fact, TNF1 mediated cellular damage in placental villous explants can be prevented by up-regulating HO activity. HO pathways have also been shown to inhibit the release of the anti-angiogenic factor, sFlt-1, in several in vitro models. Our preliminary data also indicates that chronic administration of an HO-1 enzyme inducer or a CO releasing molecule significantly attenuates hypertension in two well-established rat models of PE. Based on our preliminary data, we propose to test the central hypothesis that HO-1 and its metabolites, CO and bilirubin, attenuate the blood pressure and renal responses to placental ischemia in pregnant rats by inhibition of sFlt-l production. In addition, we propose that HO-1 derived products improve renal function and decrease total peripheral resistance and blood pressure by inhibiting the placental production of TNF1 and reactive oxygen species (ROS) and attenuating TNF1 and AT1 receptor autoantibody -induced increases in endothelial cell production of endothelin (ET-1). To test this hypothesis, arterial pressure, renal function, and endothelial factors will be examined in a conscious rat model of PE produced by long-term reductions in uterine perfusion pressure (RUPP). In addition to the RUPP model, a sFlt-1 model of PE will be used to determine the interaction between the HO-1 metabolites and sFlt-1, ET-1, and ROS production while in vitro placental explant and endothelial cell culture models will be used to examine the direct interaction of HO-metabolites in hypoxia- mediated induction of TNF, ROS and placental sFlt-1 and TNF induced ET-1 production. Specific aims are: 1) To test the hypothesis that HO-1 and its metabolites, CO and bilirubin, attenuate the blood pressure, renal, and sFlt-1 responses to placental ischemia in pregnant rats 2) To test the hypothesis that HO-1 and its metabolites, CO and bilirubin, attenuate placental ischemia and/or hypoxia-induced increases in reactive oxygen species and TNF1 3) To test the hypothesis that HO-1 and its metabolites, CO and bilirubin, attenuate TNF1 and AT1 receptor autoantibody- induced increases in ET-1 production 4) To test the hypothesis that the endogenous HO-1 pathway plays a role in regulating renal function and arterial pressure during normal pregnancy and in response to placental ischemia