Renomedullary metabolism of anandamide and blood pressure regulation

 描述（由申请人提供）：肾髓质被认为在细胞外液量和电解质的调节以及血压的长期控制中发挥关键作用。为了响应肾灌注压的增加，肾髓质被提议释放一种中性抗高血压脂质髓磷脂进入循环。该物质被认为具有三种不同的性质：在肾脏中的利钠利尿作用、血管抑制剂和中枢交感神经流出抑制剂，这些作用抵消肾脏肾素-血管紧张素-醛固酮系统的作用。到目前为止，这种物质的身份还没有被发现。在这个提议中，我们提出髓利平对应于花生四烯酸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。大麻素是一组内源性中性不饱和脂肪酸酰胺之一，由于其刺激内源性大麻素受体的能力而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。与大多数组织相比，大麻素在肾脏中的浓度较高，我们的初步研究显示，大麻素在肾髓质区富集。肾髓质也是独特的表达高组成水平的环氧合酶2（考克斯-2），一种催化花生四烯酸合成前列腺酰胺的限速步骤的酶。前列腺素E2在髓质中的形成高于皮质。这些发现与脂肪酸酰胺水解酶（Faah）的肾脏分布形成对比，Faah是将花生四烯酸和乙醇酰胺水解为花生四烯酸的酶。肾髓质比皮质表达更低的Faah蛋白和酶活性，从而促进大麻素转化为前列腺素。将大麻素输注到肾髓质中产生利尿和尿钠排泄，其作用被考克斯-2抑制剂阻断。静脉注射前列腺素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诱导的对动脉压和肾血流量的影响。本研究旨在探讨肾髓质前列腺酰胺形成与肾灌注压变化的关系。将通过使用Faah基因敲除突变小鼠对前列腺酰胺的形成进行遗传操作，这些小鼠在肾髓质、血浆和尿液中表现出前列腺酰胺水平升高。faah活性和前列腺酰胺合成也将通过遗传和化学抑制来调节。更好地了解肾髓质在长期血压控制中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.