Renomedullary metabolism of anandamide and blood pressure regulation

 描述(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。为了应对肾脏灌流压力的增加，肾髓质被建议释放一种中性的抗高血压脂质，髓磷脂，进入循环。这种物质被认为具有三种不同的性质：肾脏的利钠和利尿作用，血管降压剂和中枢交感神经流出的抑制剂，这些作用可以抵消肾脏肾素-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。在这项建议中，我们提出了延髓脂素相当于阿南达胺或其相关代谢物之一，特别是前列腺素E2的乙醇胺，也称为前列腺素E2。花椒胺是一组内源性中性不饱和脂肪酸酰胺类化合物之一，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。有几条初步证据支持前列胺代谢物代表肾髓质髓磷脂的可能性。与大多数组织相比，花青胺在肾脏中的浓度较高，在我们的初步研究中显示，它丰富了肾脏髓质区。肾脏髓质也是独一无二的，表达高组成水平的环氧合酶2(COX-2)，环氧合酶-2是一种催化苯乙酰胺合成前列胺的限速步骤的酶。髓质中的前列胺E_2生成量高于皮质。这些发现与脂肪酸酰胺水解酶(FAAH)的肾脏分布形成对比，FAAH是一种将花生胺水解酶分解为花生四烯酸和乙醇酰胺的酶。肾髓质比皮质表达较低的Faah蛋白和酶活性，从而促进花生胺向丙酰胺的转化。肾髓质内注入阿南达胺可产生利尿和利钠作用，而这种作用可被环氧合酶-2抑制剂阻断。静脉注射前列腺素E_2可降低血压，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内前列胺的形成与肾脏灌注压变化之间的关系。前列胺的形成将通过使用Faah基因敲除突变小鼠进行遗传操作，这些突变小鼠在肾髓质、血浆和尿液中表现出更高的前列胺水平。FAAH活性和前胺的合成也将受到遗传和化学抑制的调节。更好地了解肾髓质在长期控制血压中起保护作用的机制将有助于改进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.