20-HETE and its interaction with NO in pregnant rats

妊娠大鼠中20-HETE及其与NO的相互作用

• 批准号: 6531542
• 负责人: Mong-Heng Wang
• 金额: $ 4.42万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-19 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6531542
• 关键词: SDS polyacrylamide gel electrophoresis; arachidonate; blood pressure; cytochrome P450; electrolyte balance; enzyme activity; fatty acid biosynthesis; high performance liquid chromatography; immunoprecipitation; intermolecular interaction; kidney function; laboratory rat; nitric oxide; nitric oxide synthase; polymerase chain reaction; potassium channel; pregnancy; renal tubular transport; western blottings

DESCRIPTION (provided by applicant): This is a proposal to investigate the mechanisms regulating renal vascular and tubular (medullary thick ascending limb; mTAL) synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) during pregnancy. 20-HETE is a major cytochrome P450 (CYP) 4A-derived eicosanoid in the rat kidney whose potent effects on vascular tone and tubular ion transport implicate it in the regulation of renal function and in the control of blood pressure. Normal pregnancy in humans and rats is associated with increases in the glomerular filtration rate and renal blood flow along with a significant decrease in arterial pressure and total peripheral resistance. The exact mechanisms mediating these physiological changes are not fully understood. Preliminary studies demonstrated distinct patterns of CYP4A isoform expression and 20-HETE synthesis in renal microvessels and mTAL during pregnancy and a transient reduction in systolic blood pressure and urinary sodium excretion following administration of an inhibitor of 20-HETE synthesis in pregnant rats. We hypothesize that renal 20-HETE synthesis is affected during gestation and that 20-HETE is involved in the regulation of renal function and blood pressure during pregnancy. Experiments will be performed in Aim 1 to characterize vascular and mTAL 20-HETE synthesis and CYP4A expression in pregnant rats at different gestational days, and in Aim 2 to determine the consequence of inhibition and over-expression of CYP4A proteins in pregnant rats on renal 20-HETE synthesis, vascular reactivity, mTAL potassium channel activity, urinary electrolyte levels, and blood pressure. It has been shown that nitric oxide (NO) inhibits CYP4A activity and expression; inhibition of its production results in signs similar to preeclampsia. Experiments in Aims 3 and 4 will examine the possibility that NO presents a mechanism that regulates CYP4A expression and 20-HETE synthesis during pregnancy. The present proposal sets the basis for understanding mechanisms that regulate 20-HETE synthesis in the kidney during pregnancy. Ultimately, this knowledge can uncover new therapeutic targets and provide novel loci for the control and treatment of pregnancy-induced hypertension.

描述(由申请人提供)：这是一项研究怀孕期间20-羟基二十碳四烯酸(20-HETE)合成的肾血管和肾小管(髓质厚上升肢；mTAL)的机制的建议。20-HETE是大鼠肾脏中一种主要的细胞色素P450(CYP)4A来源的二十烷类化合物，其对血管张力和肾小管离子转运的强大作用与肾功能的调节和血压的控制有关。在人类和大鼠中，正常妊娠与肾小球滤过率和肾脏血流量的增加以及动脉压和总外周阻力的显着降低有关。调节这些生理变化的确切机制尚不完全清楚。初步研究表明，妊娠期大鼠肾微血管和mTAL中细胞色素P4A亚型的表达和20-HETE的合成有不同的模式，应用20-HETE合成的抑制剂后，妊娠大鼠的收缩压和尿钠排泄一过性降低。我们假设20-HETE的合成在妊娠期间受到影响，并且20-HETE参与了妊娠期间肾功能和血压的调节。目的1研究妊娠不同天数大鼠肾脏血管和mTAL 20-HETE合成及细胞色素P4A(CyP4A)的表达，目的2研究妊娠大鼠肾脏20-HETE合成、血管反应性、mTAL钾通道活性、尿电解质水平及血压的变化。已有研究表明，一氧化氮(NO)可抑制细胞色素P4A的活性和表达；抑制其产生会导致类似于先兆子痫的症状。AIMS 3和AIMS 4中的实验将检验NO是否存在调节怀孕期间CYP4A表达和20-HETE合成的机制。目前的建议为了解怀孕期间肾脏中20-HETE合成的调节机制奠定了基础。最终，这些知识可以发现新的治疗靶点，并为控制和治疗妊娠高血压综合征提供新的基因座。