20-HETE and its interaction with NO in pregnant rats

描述（由申请人提供）：这是一项研究妊娠期间调节肾血管和肾小管（髓质粗升支; mTAL）合成20-羟基二十碳四烯酸（20-HETE）的机制的提案。20-HETE是大鼠肾脏中主要的细胞色素P450（P450）4A衍生的类二十烷酸，其对血管张力和肾小管离子转运的有效作用暗示其在肾功能调节和血压控制中。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有关，沿着动脉压和总外周阻力的显著降低。介导这些生理变化的确切机制尚未完全了解。初步研究表明，妊娠期间肾脏微血管和mTAL中CYP 4A亚型表达和20-HETE合成的不同模式，以及妊娠大鼠给予20-HETE合成抑制剂后收缩压和尿钠排泄的一过性降低。我们推测，肾脏20-HETE的合成在妊娠期间受到影响，20-HETE参与妊娠期间肾功能和血压的调节。将在目的1中进行实验，以表征不同妊娠日妊娠大鼠中血管和mTAL 20-HETE合成和CYP 4A表达，并在目的2中确定妊娠大鼠中CYP 4A蛋白抑制和过度表达对肾脏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CYP 4A的活性和表达;抑制其产生导致类似于先兆子痫的体征。目的3和4中的实验将检查NO呈现在妊娠期间调节CYP 4A表达和20-HETE合成的机制的可能性。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提供新的位点。

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.