Hypertension, Kidney and Pregnancy

高血压、肾脏和怀孕

• 批准号: 8601899
• 负责人: Joey P. Granger
• 金额: $ 36.63万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8601899
• 关键词: Affect; Angiogenic Factor; Attenuated; Autoantibodies; Bilirubin; Birth; Blood Pressure; Carbon Monoxide; Cardiovascular Diseases; Cell Culture Techniques; Cessation of life; Chronic; Conscious; Coronary Arteriosclerosis; Cytoprotection; Data; Disease; End stage renal failure; Endothelial Cells; Endothelin; Endothelin-1; Enzymes; Event; Excretory function; Functional disorder; Genes; Glomerular Filtration Rate; Health; Heart failure; Hypertension; Hypoxia; In Vitro; Inflammatory; Investigation; Ischemia; Kidney; Mediating; Modeling; Morbidity - disease rate; Oxygen; Pathway interactions; Perfusion; Perinatal; Peripheral Resistance; Pharmaceutical Preparations; Placenta; Placental Growth Factor; Plasma; Play; Positioning Attribute; Pre-Eclampsia; Pregnancy; Production; Publishing; Rattus; Reactive Oxygen Species; Renal Plasma Flow; Renal function; Risk Factors; Role; Series; Stroke; TNF gene; Testing; Tissues; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factors; Villous; Woman; base; biological adaptation to stress; cell injury; cytokine; effective therapy; endothelial dysfunction; heme oxygenase-1; improved; in vitro Model; instrument; new therapeutic target; novel therapeutic intervention; peripheral blood; pregnancy hypertension; pregnant; pressure; prevent; receptor; response; vascular endothelial dysfunction

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

描述（由申请人提供）：妊娠高血压或先兆子痫 (PE) 据估计影响美国 5-7% 的妊娠。尽管它是孕产妇死亡的主要原因以及孕产妇和围产期发病率的主要原因，但目前尚无有效的药物治疗来预防PE。目前，PE唯一有效的治疗方法是早期分娩。基于最近的研究和本申请中提供的初步数据，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）和胆红素可能提供一种新的治疗方法治疗PE的方法。越来越多的证据表明，HO-1 和/或其催化产物可针对胎盘缺血（PE 病理生理学中的重要起始事件）提供细胞保护，防止细胞损伤。事实上，TNF1介导的胎盘绒毛外植体细胞损伤可以通过上调H2O2活性来预防。在一些体外模型中，HO 途径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，长期给予 HO-1 酶诱导剂或 CO 释放分子可显着减轻两种成熟的 PE 大鼠模型中的高血压。根据我们的初步数据，我们建议检验以下中心假设：HO-1 及其代谢物、CO 和胆红素通过抑制 sFlt-1 的产生来减弱怀孕大鼠的血压和肾脏对胎盘缺血的反应。此外，我们建议 HO-1 衍生产品通过抑制胎盘 TNF1 和活性氧 (ROS) 的产生以及减弱 TNF1 和 AT1 受体自身抗体诱导的内皮细胞产生增加来改善肾功能并降低总外周阻力和血压内皮素（ET-1）。为了检验这一假设，将在由子宫灌注压（RUPP）长期降低产生的有意识的PE大鼠模型中检查动脉压、肾功能和内皮因子。除了 RUPP 模型外，PE 的 sFlt-1 模型将用于确定 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确定 HO-1 代谢物与 sFlt-1、ET-1 和 ROS 产生之间的相互作用。可用于检查 H2O 代谢物在缺氧介导的 TNF、ROS 诱导以及胎盘 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) 检验 HO-1 及其代谢物、CO 和胆红素减弱妊娠大鼠胎盘缺血的血压、肾脏和 sFlt-1 反应的假设 2) 检验 HO-1及其代谢物 CO 和胆红素可减轻胎盘缺血和/或缺氧引起的活性氧和 TNF1 的增加 3) 检验 HO-1 的假设及其代谢物 CO 和胆红素，减弱 TNF1 和 AT1 受体自身抗体诱导的 ET-1 产生增加 4) 检验内源性 HO-1 途径在正常妊娠期间和妊娠期肾功能和动脉压调节中发挥作用的假设。对胎盘缺血的反应