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: 6615651
• 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/6615651
• 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）：这是研究调节肾血管和管状（髓质厚的升肢； mtal）合成20-羟基乙酸苯甲酸（20-甲基）的机制。 20-Hete是大鼠肾脏中主要的细胞色素P450（CYP）4a衍生的eicosanoid，其对血管张力和管状离子转运的有效作用与肾功能的调节和血压的控制有关。人类和大鼠的正常妊娠与肾小球过滤率和肾血流的增加以及动脉压和总周围耐药性显着降低有关。介导这些生理变化的确切机制尚不完全了解。初步研究表明，在怀孕期间，肾脏微血管和MTAL中CYP4A同工型表达和20-HETE合成的不同模式，以及在怀孕大鼠20-HETE合成的抑制剂后，收缩压和泌尿钠排泄的短暂降低。我们假设在妊娠期间会影响肾脏20-HETE的合成，并且20-HETE参与了怀孕期间肾功能和血压的调节。实验将在AIM 1中进行，以表征在不同妊娠时期怀孕大鼠中的血管和MTAL 20-HETE合成和CYP4A表达，并在AIM 2中确定肾脏20-TETE合成，血管反应性，MTAL POTASS PROLSICE和MTSTRIDER的抑制和过表达CYP4A蛋白在肾脏20-肾脏中的抑制作用和过表达。已经表明，一氧化氮（NO）抑制了CYP4A的活性和表达。抑制其生产会导致类似于先兆子痫的体征。 AIM 3和4中的实验将检查没有提出一种调节CYP4A表达和20-HETE合成的机制的可能性。本提案为理解调节怀孕期间肾脏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标，并为控制和治疗妊娠诱导的高血压提供新的基因座。