Hypertension, Kidney and Pregnancy

描述(申请人提供)：妊娠高血压综合征或先兆子痫(PE)在美国估计影响5%-7%的妊娠。尽管它是孕产妇死亡的主要原因和孕产妇和围产期发病率的主要贡献者，但没有有效的药物治疗来预防PE。目前，对PE唯一有效的治疗方法是早产。根据最近的研究和应用中的初步数据，我们认为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途径。越来越多的证据表明，HO-1和/或其催化产物对胎盘缺血所致的细胞损伤具有细胞保护作用，这是PE病理生理过程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活性来防止。在几种体外模型中，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，长期服用HO-1酶诱导剂或CO释放分子可显著降低两种已建立的PE大鼠模型的高血压。根据我们的初步数据，我们建议检验HO-1及其代谢物CO和胆红素，通过抑制sFlt-L的产生来减轻妊娠大鼠对胎盘缺血的血压和肾脏反应的中心假设。此外，我们认为，HO-1衍生产品可通过抑制胎盘组织中TNF1和ROS的产生，以及减轻TNF1和AT1受体自身抗体诱导的内皮细胞分泌内皮素(ET-1)的增加，从而改善肾功能，降低外周阻力和血压。为了验证这一假设，将在长期降低子宫灌注压(RUPP)所产生的PE的清醒大鼠模型中检测动脉压、肾功能和内皮因子。除了RUPP模型外，还将使用PE的sFlt-1模型来确定HO-1代谢产物与sFlt-1、ET-1和ROS的产生之间的相互作用，而在体外胎盘组织和内皮细胞培养模型中，将研究HO-代谢物在低氧诱导的TNF、ROS和胎盘sFlt-1和TNF诱导的ET-1产生中的直接相互作用。具体目的是：1)检验HO-1及其代谢产物CO和胆红素减弱妊娠大鼠对胎盘缺血的血压、肾脏和sFlt-1反应的假设2)检验HO-1及其代谢产物CO和胆红素减轻胎盘缺血和/或缺氧诱导的活性氧和TNF1增加的假说3)检验HO-1及其代谢产物CO和胆红素，减弱TNF1和AT1受体自身抗体诱导的ET-1生成增加4)验证内源性HO-1途径在正常妊娠期间和胎盘缺血反应中调节肾功能和动脉压的假设 公共卫生相关性：高血压，如先兆子痫(PE)，长期以来一直被认为是心血管疾病的主要危险因素，包括冠状动脉疾病、心力衰竭和中风，以及ESRD。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贡献者，但没有有效的药物治疗来预防PE。根据本申请提供的初步数据，我们认为，诱导血红素加氧酶-1及其催化产物一氧化碳和胆红素可能为PE的治疗提供一种新的治疗方法。

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 PUBLIC HEALTH RELEVANCE: Hypertension, as seen in preeclampsia (PE), has long been recognized as a major risk factor for cardiovascular diseases, including coronary artery disease, heart failure and stroke, and for ESRD. 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. Based on preliminary data presented in this application, we propose that induction of hemeoxygenase-1 and its catalytic products, carbon monoxide and bilirubin, may provide a novel therapeutic approach for the treatment of PE.