REGULATION OF RENAL FUNCTION AND BP BY THROMBOXANE

血栓烷对肾功能和血压的调节

基本信息

批准号：
7990209
负责人：
CHRISTOPHER S WILCOX
金额：
$ 7.83万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-15 至 2010-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7990209
关键词：
Abbreviations Acetylcholine Acids Agonist Anesthesia procedures Biological Preservation Blood Vessels Caliber Cells Choline Conscious Controlled Environment Dinoprostone Dose Duct (organ) structure Endothelin-1 Endothelium Epoprostenol Equilibrium Excretory function Extracellular Fluid Feedback Figs - dietary Filtration Fluorescent Probes Generations Glomerular Capillary Glomerular Filtration Rate Glossary Homeostasis Hypertension Isoprostanes Juxtaglomerular Apparatus Kidney Knock-out Ligands Limb structure Macula densa Measures Mediating Mediator of activation protein Messenger RNA Metabolism Micropuncture Mus Muscle Cells NADPH Oxidase Nephrons Nitric Oxide Nitric Oxide Donors Nitric Oxide Synthase Type I Norepinephrine Oxidation-Reduction Oxidative Stress Pathway interactions Peroxonitrite Process Production Prostacyclin synthase Prostaglandin Endoperoxides Prostaglandin H2 Prostaglandin H2 Receptor Prostaglandin-Endoperoxide Synthase Prostaglandins I Protocols documentation Rattus Reaction Receptor Activation Receptor Gene Regulation Relative (related person)Relaxation Renal function Renin-Angiotensin-Aldosterone System Research Personnel Resistance Role Signal Pathway Smooth Muscle Myocytes Sodium Sodium Chloride Sodium-Restricted Diet Stress Superoxides System Telemetry Testing Thick Thromboxane A2 Thromboxane Receptor Thromboxanes Tubular formation Vascular resistance Vasoconstrictor Agents Vasodilator Agents arteriole cyclooxygenase 1 cyclooxygenase 2 hemodynamics ifetroban in vivo inhibitor/antagonist kidney cortex kidney vascular structure mimetics pressure prevent progesterone 11-hemisuccinate-(2-iodohistamine)programs protein expression response salt balance salt intake salt sensitive solute tempol vasoconstriction

项目摘要

Vasoconstrictor PGs activating the TP receptor (R) include PGH2, TxA2 and isoprostanes (Iso). NO or peroxynitrite (ONOO), its reaction product with superoxide anion (02"'), can activate cyclooxygenase (COX) whereas O2""and ONOO can inactivate prostacyclin synthase (PGIz-S), activate TxAz synthase and generate Iso, thereby promoting vasoconstrictor PG mechanisms. The specific roles of COX-1 vs. -2, and the diverse agonists of the TP-R and their role in the regulation of microvascular resistance, salt balance and BP remain unclear. This is the focus of this proposal. Specific Aim I will utilize COX-1 and TP-R gene deleted mice, and specific COX-2 antagonists to investigate the hypothesis that these systems have discrete roles in normal homeostasis by adjusting salt excretion, renal microvascular resistance, tubuloglomerular feedback (TGF) and proximal NaCI reabsorption to stabilize BP and prevent salt sensitivity during changes in salt intake. Specific Aim II will investigate the hypothesis that neuronal nitric oxide synthase (nNOS)- derived NO generated during macula densa (MD) solute reabsorption activates COX-2 dependent signaling pathway from the MD that regulates afferent arteriolar tone via release of PGH2. PGH2 can be metabolized to vasodilator PG's that limit vasoconstrictor TGF responses, but during Ang II action, PGI2-S is blocked, and PGH2, Iso and TxA2 activate TP-R-dependent enhancement of TGF, thereby assisting in salt and volume preservation. Specific Aim III will investigate the hypothesis that a COX- and TP-R-dependent process enhances vasoconstriction to Ang II and diminishes vasodUation to acetylcholine of the renal afferent arteriole of mice undergoing an Ang II slow pressor response. These studies are focused on the roles of COX-1 vs. -2, and TP-R in mediating renal mechanism of homeostasis and their dysregulation during Ang II hypertension.

激活 TP 受体 (R) 的血管收缩剂 PG 包括 PGH2、TxA2 和异前列烷 (Iso)。否或过氧亚硝酸盐（ONOO），其与超氧阴离子（02"'）的反应产物，可以激活环氧合酶（COX）而 O2"" 和 ONOO 可以使前列环素合酶 (PGIz-S) 失活，激活 TxAz 合酶并生成Iso，从而促进血管收缩PG机制。 COX-1 与 -2 的具体作用，以及 TP-R 的多种激动剂及其在调节微血管阻力、盐平衡和血压仍不清楚。这是本提案的重点。具体目标我将利用COX-1和TP-R基因缺失的小鼠和特定的 COX-2 拮抗剂来研究这些系统具有离散的假设通过调节盐排泄、肾微血管阻力、肾小球肾小球在正常体内平衡中的作用反馈 (TGF) 和近端 NaCl 重吸收，以稳定血压并防止变化过程中的盐敏感性在盐的摄入量中。具体目标 II 将研究神经元一氧化氮合酶 (nNOS) 的假设 - 致密斑 (MD) 溶质重吸收过程中产生的衍生 NO 激活 COX-2 依赖性信号传导 MD 通路通过释放 PGH2 调节传入小动脉张力。 PGH2可以被代谢血管扩张剂 PG 限制血管收缩剂 TGF 反应，但在 Ang II 作用期间，PGI2-S 被阻断，并且 PGH2、Iso 和 TxA2 激活 TP-R 依赖性 TGF 增强，从而有助于盐和体积保存。具体目标 III 将研究 COX 和 TP-R 依赖性过程的假设增强血管紧张素II的血管收缩并减少肾传入乙酰胆碱的血管舒张经历 Ang II 慢升压反应的小鼠的小动脉。这些研究的重点是 COX-1 vs. -2 和 TP-R 在介导 Ang II 期间肾脏稳态机制及其失调中的作用高血压。