Renomedullary metabolism of anandamide and blood pressure regulation

描述（由申请人提供）：肾髓质被认为在调节细胞外液容量和电解质以及长期控制血压方面起着关键作用。为了应对肾灌注压力的增加，肾髓质被提议释放中性降压脂质髓质进入循环。该物质被认为具有三种不同的特性：在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，这些作用抵消肾素-血管紧张素-醛固酮系统的作用。这种物质的性质至今尚未查明。在本提案中，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prostamide E2。Anandamide是一组内源性中性不饱和脂肪酸酰胺中的一种，因其能够刺激内源性大麻素受体而被统称为内源性大麻素。前列胺代谢物代表肾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，Anandamide以高浓度存在于肾脏中，并且在我们的初步研究中显示在肾髓质区域富集。肾髓质在表达高组成水平的环氧化酶2 （Cox-2）方面也是独一无二的，环氧化酶2是一种催化从大麻酰胺合成prostamides的限速步骤的酶。髓质中E2的形成量高于皮质。这些发现与脂肪酸酰胺水解酶（FAAH）的肾脏分布相反，FAAH是一种将花生四烯酸和乙醇酰胺水解成花生四烯酸的酶。肾髓质表达Faah蛋白和酶活性低于皮质，从而促进了anandamide向prostamide的转化。anandamide输注到肾髓质产生利尿和尿钠，作用被Cox-2抑制剂阻断。静脉注射prostamide E2降低血压，增加肾血流量，其作用直接抵消血管紧张素ii对动脉压和肾血流量的影响。本研究旨在探讨肾髓质中前列腺胺的形成与肾灌注压变化的关系。通过使用Faah基因敲除突变小鼠来控制前列腺素的形成，这些小鼠在肾髓质、血浆和尿液中显示出增加的前列腺素水平。Faah活性和丙胺合成也会受到遗传和化学抑制的调节。更好地了解肾髓质对血压长期控制的保护机制将有助于改善高血压的预防和治疗。

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.