mPGES-1/EP1 in volume regulation

mPGES-1/EP1 在音量调节中的作用

• 批准号: 8398952
• 负责人: Tianxin Yang
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8398952
• 关键词: Affect; Aldosterone; Analgesics; Anti-Inflammatory Agents; Anti-inflammatory; Attention; Attenuated; Blood Pressure; Cardiovascular system; Couples; Dinoprostone; Distal; Diuretics; Edema; Enzymes; Equilibrium; Excretory function; Exhibits; Extracellular Fluid; Hand; Hypernatremia; Hypertension; Inflammation; Inflammatory Response; Infusion procedures; Intake; Investigation; Isomerase; Kidney; Light; Liquid substance; Marketing; Mediating; Molecular; Molecular Target; Mus; Natriuresis; PTGS2 gene; Pain; Pathway interactions; Perfusion; Pharmaceutical Preparations; Phenotype; Physiological; Physiological Processes; Play; Process; Production; Property; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Publishing; Regulation; Renal function; Renal tubule structure; Role; Safety; Site; Sodium Chloride; Steroids; Therapeutic; Toxic effect; Tubular formation; Water; in vivo; inhibitor/antagonist; kidney cell; next generation; novel; pressure; prostaglandin E synthase-1; prostanoid receptor EP1; response; saluretic; urinary

DESCRIPTION (provided by applicant): Summary: The kidney plays a major role in the regulation of extracellular fluid volume (ECFV) and blood + + pressure (BP) via adjustment of urinary Na excretion in alignment with Na intake. Despite intensive + investigation, the molecular mechanism of renal handing of Na and water balance is still imperfectly understood. A large body of evidence demonstrates that PGE2 is an important regulator of renal function + due to its natriuretic and diuretic properties. In isolated microperfused renal tubules, PGE2 inhibits Na and water transport. Moreover, the inhibition of prostanoid synthesis with Non-Steroid Anti-inflammatory Drugs (NSAIDs) or COX-2 inhibitors is associated with cardiovascular consequences, including hypertension and edema formation. Microsomal prostaglandin E synthase-1 (mPGES-1) has been characterized as the only isomerase processing the in vivo PGES activity and is critically involved in the pain and inflammatory responses. In recent years, mPGES-1 has received a great attention due to the promise for serving as a novel target for anti-inflammatory drugs. The lesson from COX-2 inhibitors has prompted a thorough examination of the role of mPGES-1 in physiological processes. Our published studies demonstrate that mPGES-1 KO mice exhibit impaired natriuretic/diuretic responses to salt loading and also fail to undergo aldosterone (Aldo) escape. The phenotype was recapitulated by EP1 antagonism. We hypothesize that renal mPGES-1/ EP1 pathway responds to a rise in renal perfusion pressure (RPP) + during ECFV expansion and elicits natriuresis through inhibition of renal Na transport thereby + attenuating Na retention and hypertension. We propose to define the role of mPGES-1- and EP1 receptors under two different volume expansion states induced by Aldo infusion and high salt loading. Major experimental approaches involve the production and analysis of mice with renal cell-deletion of mPGES-1 and EP1 as well as the examination of RPP as a regulator of renal PGE2 synthesis. There are 3 specific aims: 1) to investigate the influence of systemic mPGES-1 deletion on volume regulation, 2) to investigate the influence of site-specific mPGES-1 inhibition on volume regulation, and 3) to investigate the role of EP1 in volume regulation. New information resulted from this proposal will help define PGE cascades in the control of ECFV.

描述（由申请人提供）： 总结：肾脏通过调整尿钠排泄与钠摄入量，在细胞外液容量（ECFV）和血压（BP）的调节中起主要作用。尽管进行了深入的研究，但肾脏处理钠和水平衡的分子机制仍不完全清楚。大量证据表明，PGE 2是肾功能的重要调节剂+，因为它具有利钠和利尿特性。在离体微灌注肾小管中，PGE 2抑制Na和水的转运。此外，用非甾体抗炎药（NSAID）或考克斯-2抑制剂抑制前列腺素类合成与心血管后果相关，包括高血压和水肿形成。微粒体前列腺素E合酶-1（mPGES-1）是唯一的体内异构酶，参与疼痛和炎症反应。近年来，mPGES-1由于有望作为抗炎药物的新靶点而受到极大关注。从考克斯-2抑制剂的教训，促使mPGES-1在生理过程中的作用进行了彻底的检查。我们发表的研究表明，mPGES-1 KO小鼠表现出受损的钠尿/利尿反应盐负荷，也未能进行醛固酮（Aldo）逃逸。表型通过EP 1拮抗作用重现。我们推测，肾mPGES-1/EP 1途径通过抑制肾Na转运，从而减轻Na+潴留和高血压，对ECFV扩张期间肾灌注压（RPP）+的升高做出反应。我们建议定义mPGES-1-和EP 1受体的作用下两个不同的体积膨胀状态诱导的阿尔多输液和高盐负荷。主要的实验方法包括生产和分析mPGES-1和EP 1肾细胞缺失的小鼠，以及检查RPP作为肾脏PGE 2合成的调节剂。有三个具体目标：1）研究系统性mPGES-1缺失对容量调节的影响，2）研究位点特异性mPGES-1抑制对容量调节的影响，3）研究EP 1在容量调节中的作用。新的信息，从这个建议将有助于确定铂族元素级联的控制ECFV。