REGULATION OF RENAL FUNCTION AND BP BY THROMBOXANE

血栓烷对肾功能和血压的调节

• 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
• 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

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）。没有或 过氧亚硝基阴离子（ONOO）是其与超氧阴离子（O2 "'）反应的产物，可激活环氧合酶（考克斯）， 而O_2~（2-）和ONOO则能抑制前列环素合成酶（PGIz-S），激活TxAz合成酶， 产生Iso，从而促进血管收缩剂PG机制。考克斯-1与-2的具体作用，以及 TP-R的不同激动剂及其在微血管阻力、盐平衡和 英国石油公司仍不清楚。这是本提案的重点。具体目的I将利用考克斯-1和TP-R基因 缺失小鼠和特异性考克斯-2拮抗剂来研究这些系统具有离散的 通过调节盐排泄、肾微血管阻力、肾小管肾小球 反馈（TGF）和近端NaCl重吸收，以稳定BP并防止变化期间的盐敏感性 盐的摄入量。具体目标II将研究神经元型一氧化氮合酶（nNOS）- 在致密斑（MD）溶质重吸收过程中产生的衍生NO激活考克斯-2依赖性信号传导 通过释放PGH2调节传入小动脉张力的MD通路。PGH2可被代谢 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， PGH2、Iso和TxA2激活TGF的TP-R依赖性增强，从而辅助盐和容量 保存。具体目标III将研究考克斯-和TP-R-依赖性过程的假设， 增强血管紧张素Ⅱ的收缩作用，减少肾传入神经对乙酰胆碱的血管调节作用 小鼠的小动脉经历血管紧张素II缓慢升压反应。这些研究的重点是 考克斯-1 vs.-2和TP-R在血管紧张素Ⅱ肾内稳态调节中的作用 高血压