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: 6765318
• 负责人: Mong-Heng Wang
• 金额: $ 24.6万
• 依托单位: AUGUSTA UNIVERSITY
• 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 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6765318
• 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）：本研究旨在探讨妊娠期间肾血管和小管（髓质增厚升肢；tal）合成20-羟基二碳四烯酸（20-HETE）的机制。20-HETE是大鼠肾脏中一种主要的细胞色素P450 (CYP) 4a衍生的类二十烷酸，其对血管张力和小管离子运输的强大作用使其参与肾功能的调节和血压的控制。人类和大鼠的正常妊娠与肾小球滤过率和肾血流量的增加以及动脉压和总外周阻力的显著降低有关。介导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tal中CYP4A异构体表达和20-HETE合成的不同模式，以及服用20-HETE合成抑制剂后收缩压和尿钠排泄的短暂降低。我们假设妊娠期间肾脏20-HETE的合成受到影响，并且20-HETE参与了妊娠期间肾功能和血压的调节。实验将在Aim 1中进行，以表征不同妊娠期妊娠大鼠血管和mTAL中20-HETE的合成和CYP4A的表达。实验将在Aim 2中进行，以确定妊娠大鼠CYP4A蛋白的抑制和过表达对肾脏20-HETE合成、血管反应性、mTAL钾通道活性、尿电解质水平和血压的影响。研究表明，一氧化氮（NO）抑制CYP4A活性和表达；抑制其产生会导致类似子痫前期的症状。Aims 3和Aims 4的实验将探讨NO在妊娠期间调节CYP4A表达和20-HETE合成的可能性。目前的建议为理解在妊娠期间调节肾脏中20-HETE合成的机制奠定了基础。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性高血压提供新的基因位点。