Renomedullary metabolism of anandamide and blood pressure regulation

anandamide 的肾髓代谢与血压调节

• 批准号: 8852753
• 负责人: PinLan Li
• 金额: $ 9.15万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-10 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8852753
• 关键词: Abbreviations; Address; Affect; Amides; Angiotensin II; Antihypertensive Agents; Applications Grants; Arachidonic Acids; Arteries; Biochemical; Blood; Blood Circulation; Blood Pressure; CNR1 gene; Cannabinoids; Coxibs; Dinoprostone; Disodium Salt Nitroprusside; Diuresis; Diuretics; Drug Addiction; Electrolytes; Endocannabinoids; Enzymes; Excretory function; Exhibits; Extracellular Fluid; Health; Heart Diseases; Hydrolysis; Hypertension; Hypotension; Inflammation; Infusion procedures; Intravenous; Kidney; Kidney Failure; Knock-out; Lipids; Liquid substance; 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; Relative (related person); Renal Blood Flow; Renin-Angiotensin-Aldosterone System; Resistance; Role; Shunt Device; Sodium; Stimulus; Stroke; Sympatholytics; System; Tissues; United States; Unsaturated Fatty Acids; Urine; Vasodilation; Vasodilator Agents; Work; anandamide; 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 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。为了响应肾灌注压的增加，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：肾脏中的利钠和利尿作用、血管抑制剂和中枢交感神经流出抑制剂，这些作用抵消了肾素-血管紧张素-醛固酮系统的作用。迄今为止，这种物质的身份尚未揭晓。在此提案中，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。 Anandamide 是一组内源性中性不饱和脂肪酸酰胺中的一种，由于它们能够刺激内源性大麻素受体，因此统称为内源性大麻素。前列腺酰胺代谢物代表肾髓质髓磷脂的可能性得到了几条初步证据的支持。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肾髓质区域。肾髓质在表达高水平的环加氧酶 2 (Cox-2) 方面也是独一无二的，这种酶催化从 anandamide 合成前列腺酰胺的限速步骤。髓质中前列腺酰胺 E2 的形成量高于皮质。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，FAAH 是将花生四烯酸和乙醇酰胺水解成花生四烯酸和乙醇酰胺的酶。肾髓质表达的 Faah 蛋白和酶活性低于皮质，从而促进 anandamide 转化为前列腺酰胺。将 anandamide 输注到肾髓质中会产生利尿和尿钠排泄的作用，但这种作用会被 Cox-2 抑制剂阻断。静脉注射前列腺酰胺E2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。该提案旨在研究肾髓质中前列腺酰胺的形成与肾灌注压变化之间的关系。前列腺酰胺的形成将通过使用 Faah 敲除突变小鼠进行基因操纵，这些小鼠的肾髓质、血浆和尿液中的前列腺酰胺水平增加。 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。更好地了解肾髓质中长期控制血压的保护机制将有助于改善高血压的预防和治疗。