REGULATION OF RENAL FUNCTION AND BP BY THROMBOXANE

激活TP受体(R)的血管收缩药PG包括PGH2、TXA2和异前列腺素(Iso)。否或 过氧亚硝酸盐(ONOO)与超氧阴离子(02“‘)反应生成的过氧亚硝酸盐(ONOO)能激活环氧合酶(COX)。 而O2“”和ONOO可以灭活前列环素合成酶(PGIz-S)，激活TxAz合成酶，并 产生Iso，从而促进血管收缩PG机制。COX-1与COX-2的具体作用，以及 不同的TP-R激动剂及其在调节微血管阻力、盐平衡和血管紧张素转换酶中的作用 英国石油公司目前仍不清楚。这是这项提案的重点。特定目的I将利用COX-1和TP-R基因 删除小鼠和特定的COX-2拮抗剂，以调查这些系统具有离散 调节盐分排泄、肾微血管阻力、肾小管球蛋白在正常内环境稳定中的作用 反馈(转化生长因子)和近端NaCI重吸收以稳定血压并防止变化期间的盐敏感性 在盐分摄入量方面。特定目标II将调查神经元型一氧化氮合酶(NNOS)- 致密斑(MD)溶质重吸收过程中产生的NO激活COX-2依赖的信号转导 MD通过释放PGH2调节传入小动脉张力的途径。前列环素可以被代谢 血管扩张剂PG可限制血管收缩因子转化生长因子的反应，但在血管紧张素II的作用中，PGI2-S被阻断，并且 PGH2、Iso和TXA2激活TP-R依赖的转化生长因子增强，从而辅助盐和容量 保护。特定目标III将研究COX和TP-R依赖的过程的假设 增强肾传入纤维对血管紧张素Ⅱ的收缩作用和减少对乙酰胆碱的血管收缩作用 血管紧张素Ⅱ缓慢升压反应小鼠的微动脉。这些研究的重点是 环氧合酶-1与环氧合酶-2和TP-R在介导肾脏动态平衡机制中的作用及其在血管紧张素Ⅱ中的失调 高血压。

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.