Renomedullary metabolism of anandamide and blood pressure regulation

anandamide 的肾髓代谢与血压调节

• 批准号: 9054518
• 负责人: PinLan Li
• 金额: $ 33.79万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-15 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9054518
• 关键词: Address; Affect; Amides; Angiotensin II; Antihypertensive Agents; Applications Grants; Arachidonic Acids; Arteries; Biochemical; Blood Circulation; Blood Pressure; Blood flow; CNR1 gene; Chronic; Coxibs; Dinoprostone; Diuresis; Diuretics; Drug Addiction; Electrolytes; Endocannabinoids; Endocrine; Enzymes; Equilibrium; Exhibits; Extracellular Fluid; Health; Heart; Heart Diseases; Hypertension; Hypotension; Infusion procedures; Intravenous; Kidney; Kidney Failure; Knock-out; Lipids; Mediating; Metabolism; Modeling; Molecular; Mus; Mutant Strains Mice; Natriuresis; Obesity; Pathologic; Pathway interactions; Perfusion; Physiological; Plasma; Play; Prevention; Production; Property; Prostaglandins; Proteins; Public Health; Regulation; Renal Blood Flow; Renin-Angiotensin-Aldosterone System; Resistance; Role; Sodium; Stimulus; Stroke; System; Tissues; Tubular formation; United States; Unsaturated Fatty Acids; Urine; Vasodilation; Water; Work; anandamide; blood pressure reduction; blood pressure regulation; cannabinoid receptor; chemical genetics; cyclooxygenase 2; drug reward; energy balance; enzyme activity; fatty acid amide hydrolase; gene therapy; hypertension treatment; improved; inhibitor/antagonist; kidney interstitial tissue; kidney medulla; pressure; prevent; response; saluretic

 DESCRIPTION (provided by applicant): The renal medulla is considered to play a critical role in the regulation of extracellular fluid volume and electrolytes and long-term control of blood pressure. In response to an increase in renal perfusion pressure, the renal medulla is proposed to release a neutral antihypertensive lipid, medullipin, into the circulation. This substance is proposed to have three distinct properties: natriuretic and diuretic action in the kidney, vasodepressor, and inhibitor of central sympathetic outflow, actions which counteract those of the renal renin- angiotensin-aldosterone system. The identity of this substance has so far not been uncovered. In this proposal, we propose that medullipin corresponds to anandamide or one of its associated metabolites, in particular, the ethanolamide of prostaglandin E2 also called prostamide E2. Anandamide is one of a group of endogenous neutral unsaturated fatty acid amides collectively known as endocannabinoids due to their ability to stimulate endogenous cannabinoid receptors. The possibility that prostamide metabolites represent renal medullary medullipin is supported by several lines of preliminary evidence. Anandamide is present in the kidneys at high concentration relative to most tissues and was shown in our preliminary studies to be enriched the renal medullary region. The kidney medulla is also unique in expressing high constitutive levels of cyclooxygenase 2 (Cox-2), an enzyme that catalyzes the rate-limiting step in synthesis of prostamides from anandamide. Prostamide E2 formation is higher in the medulla than cortex. These findings contrast with the renal distribution of fatty acid amide hydrolase (Faah), the enzyme that hydrolyzes anandamide to arachidonic acid and ethanolamide. The renal medulla expresses lower Faah protein and enzyme activity than cortex, thereby facilitating the conversion of anandamide to prostamide. Infusion of anandamide into the renal medulla produces diuresis and natriuresis, effects which are blocked by a Cox-2 inhibitor. Intravenous prostamide E2 lowers blood pressure and increases renal blood flow, and its effects directly counteract angiotensin II-induced effects on arterial pressure and renal blood flow. This proposal aims to investigate the relationship between prostamide formation in the renal medulla and changes in renal perfusion pressure. The formation of prostamides will be manipulated genetically by using Faah knockout mutant mice, which exhibit increased levels of prostamides in renal medulla, plasma, and urine. Faah activity and prostamide synthesis will also be modulated by genetic and chemical inhibition. A better understanding of mechanisms in the renal medulla that are protective in the long-term control of blood pressure will result in improved prevention and treatment of hypertension.

 描述（由适用提供）：肾脏髓质被认为在调节细胞外液体积和电解质以及对血压的长期控制中起关键作用。为了响应肾脏灌注压力的升高，提出了肾脏髓质，以释放中性的抗高血压脂质髓质蛋白髓质脂蛋白。该物质被认为具有三种不同的特性：肾脏，血管抑制剂和中枢交感神经输出的抑制剂中的亚钠和利尿作用，这些作用抵消了肾素肾素 - 血管紧张素 - 醛固酮系统的作用。到目前为止，该物质的身份尚未发现。在该提议中，我们建议髓脂素对应于anandamide或其相关的代谢产物之一，特别是前列腺素E2的乙醇酰胺也称为Prostamide E2。阿甘丹酰胺是一组内源性中性的不饱和脂肪酸辅助物之一，由于它们具有刺激内源性大麻素受体的能力，因此被称为内源性大麻素。前列腺酰胺代谢产物代表肾髓质髓质的可能性得到了几条初步证据的支持。相对于大多数组织，小浓度的Kidsneys中存在Anandamide，并在我们的初步研究中得到了富含肾脏髓质区域的表现。环氧酶2（COX-2），一种酶，可催化从anandamide合成前列腺酰胺的限制步骤。髓质中的前列腺酰胺E2的形成高于皮层。这些发现与脂肪酸酰胺水解酶（FAAH）的肾脏分布形成鲜明对比，该酶将anandamide水解为花生四烯酸和乙醇酰胺。肾髓质比皮质表达较低的FAAH蛋白和酶活性，从而支持Anandamide转化为前列腺酰胺。将anandamide输注到肾脏髓质中会产生利尿和纳地尿液，这些作用被COX-2抑制剂阻塞。静脉注射前列腺酰胺E2降低血压并增加肾血流，其作用直接抵消血管紧张素II诱导的对动脉压和肾血流的影响。该建议旨在研究肾脏髓质中前列腺酰胺形成与肾脏灌注压力变化之间的关系。使用FAAH基因敲除突变小鼠，将前列腺酰胺的形成进行遗传操纵，后者暴露了肾脏髓质，血浆和尿液中前列腺酰胺水平的增加。 FAAH活性和前列腺酰胺合成也将受到遗传和化学抑制的调节。对在长期控制血压中受到保护的肾脏延髓机制的更好理解将改善预防和治疗高血压。