Hypertension, Kidney and Pregnancy

高血压、肾脏和怀孕

• 批准号: 8247752
• 负责人: Joey P. Granger
• 金额: $ 37.38万
• 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/8247752
• 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; Hypertension induced by pregnancy; 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; heme oxygenase-1; improved; in vitro Model; instrument; new therapeutic target; novel therapeutic intervention; peripheral blood; 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 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.

描述（由申请人提供）：据估计，妊娠诱发的高血压或先兆子痫（PE）会影响美国所有怀孕的5-7％，尽管它是孕产妇死亡的主要原因，并且主要促进了孕产妇和围产期发病率的主要原因，但没有有效的药物治疗可防止PE。目前，PE的唯一有效治疗方法是早期分娩。基于最新的研究和本应用中介绍的初步数据，我们建议诱导应力反应基因，血氧酶-1（HO-1）及其催化产物，一氧化碳（CO）和胆红素，可以为PE治疗提供一种新型的治疗方法。有越来越多的证据表明，HO-1和/或其催化产物可赋予细胞损伤的细胞保护作用，以响应胎盘缺血，这是PE的病理生理学中的重要起始事件。实际上，可以通过上调HO活性来预防TNF1介导的胎盘绒毛外植体中的细胞损伤。 HO途径还显示出在几种体外模型中抑制抗血管生成因子SFLT-1的释放。我们的初步数据还表明，在两个公认的PE大鼠模型中，长期施用HO-1酶诱导剂或CO释放分子可显着减轻高血压。根据我们的初步数据，我们建议测试HO-1及其代谢产物CO和胆红素的中心假设，通过抑制SFLT-L产量来减轻怀孕大鼠胎盘缺血的血压和肾脏反应。此外，我们建议HO-1衍生的产物通过抑制TNF1和活性氧（ROS）的胎盘产生（ROS）以及减弱TNF1和AT1受体自身抗体诱导的内皮细胞产生（ET-1）的增加，从而改善了肾功能并降低总周围耐药性和血压。为了检验这一假设，将在长期降低子宫灌注压力（RUPP）中产生的有意识的PE大鼠模型中检查动脉压，肾功能和内皮因子。除RUPP模型外，PE的SFLT-1模型还将用于确定HO-1代谢产物与SFLT-1，ET-1和ROS产生之间的相互作用，而在体外胎盘层层层植物和内皮细胞培养模型中，将用于检查Ho-Metabolites在TNF，ROS和Pastental SfleStental Sfl，Splt，Splt Tnf Tnf诱导中Ho-Metabolites在低氧介导的诱导中的直接相互作用。具体目的是：1）检验以下假设：HO-1及其代谢物（CO和胆红素）衰减怀孕大鼠的血压，肾脏和SFLT-1对胎盘缺血的反应2）测试HO-1的假说，即HO-1及其代谢物，CO和胆红素的增长量和胆红素的增长量，并抑制了胎盘 - 含量不足。 3）为了测试HO-1及其代谢产物CO和胆红素的假设，减轻TNF1和AT1受体自身抗体诱导的ET-1产量增加4），以检验内源性HO-1途径在调节肾功能和动脉压力下在正常怀孕期间和动脉压力中起作用的假设 公共卫生相关性：在先兆子痫（PE）中看到的高血压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，也是导致孕产妇和围产期发病率的主要贡献者，但仍没有有效的药物治疗可以预防PE。基于本应用程序中介绍的初步数据，我们建议诱导Hemeoxygenase-1及其催化产物一氧化碳和胆红素可能为PE治疗提供一种新型的治疗方法。