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（申请人提供）：肾髓质被认为在细胞外液容量和电解质的调节以及血压的长期控制中发挥着关键作用。针对肾灌注压的增加，提出了肾髓质。将中性抗高血压脂质髓磷脂释放到循环中，该物质被认为具有三种不同的特性：肾脏利钠和利尿作用、血管抑制剂和抑制剂。中枢交感神经流出的作用，抵消肾素-血管紧张素-醛固酮系统的作用。迄今为止，该物质的身份尚未被揭示。在该提议中，我们提出髓磷脂对应于 anandamide 或其相关代谢物之一。特别是，前列腺素 E2 的乙醇酰胺也称为前列腺酰胺 E2，是一组内源性中性不饱和脂肪酸酰胺中的一种，由于其能够产生内源性大麻素，因此统称为内源性大麻素。刺激内源性大麻素受体。多项初步证据支持前列腺酰胺代谢物代表肾髓质磷脂的可能性，相对于大多数组织，大麻素以高浓度存在于肾脏中，并且在我们的初步研究中显示其富集于肾髓质区域。肾髓质在表达高组成水平的环氧合酶 2 (Cox-2) 方面也是独一无二的，该酶是一种催化限速步骤的酶前列腺酰胺 E2 的形成在髓质中高于皮质，这与脂肪酸酰胺水解酶 (Faah) 的肾脏分布形成对比，脂肪酸酰胺水解酶将花生四烯酸和乙醇酰胺水解为肾髓质。 Faah蛋白和酶的活性高于皮质，有利于anandamide转化为prostamide，将anandamide输注到肾髓质产生利尿作用。排尿钠，被 Cox-2 抑制剂阻断的作用可降低血压并增加肾血流量，其作用直接抵消血管紧张素 II 引起的动脉压和肾血流量的影响。肾髓质中前列腺酰胺的形成与肾灌注压变化之间的关系将通过使用 Faah 敲除突变小鼠来基因控制前列腺酰胺的形成，该小鼠表现出肾脏中前列腺酰胺水平的增加。肾髓质、血浆和尿液的 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。更好地了解肾髓质中对长期控制血压的保护机制将有助于改善预防和治疗。高血压。