CYTOCHROME P-450 ARACHIDONIC ACID METABOLISM & REGULATION OF RENAL ION TRANSPORT

CYTOCHROME P-450 花生四烯酸代谢

• 批准号: 6270655
• 负责人: Matthew Douglas Breyer
• 金额: $ 5.6万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6270655
• 关键词: cyclic AMP; cytochrome P450; dietary sodium; eicosanoid metabolism; female; human subject; hypertension; ion transport; kidney function; laboratory rabbit; laboratory rat; microelectrodes; microsomes; pregnancy; pregnancy toxemia /hypertension; prostaglandin endoperoxide synthase; prostaglandin inhibitors; prostaglandin receptor; renal tubule; tissue /cell culture; voltage /patch clamp

It is now clear that certain arachidonate metabolites that derive from cytochrome P-450 (CP-450) metabolism have important effects on ion and water transport in the mammalian kidney. What is currently less clear is the physiologic and pathophysiologic importance of this pathway in regulating the kidney's contribution to salt and water balance. There are, however, a number of compelling observations which call for a thorough analysis of the functional significance of CP-450 arachidonate metabolism in the regulation of sodium reabsorption by the kidney. These observations are basically from models of experimental hypertension. In the spontaneously hypertensive rat (SHR), McGiff, Schwartzman, Abraham and their colleagues have implicated a role for omega and omega-1 hydroxylation of arachidonic acid in the development of hypertension. The functional link, however, remains unclear. In studies from our group, it appears that dietary salt loading markedly induces epoxygenase activity in the normal rat, but not in the Dahl salt-sensitive genetic strain of rat. Again, the functional link in the Dahl salt-sensitive animal has not been elucidated. Although data in hypertensive animal models provide a major impetus for studying the regulation of sodium transport by cytochrome P-450 metabolites, we are confident that these compounds will play an important role in the normal handling of sodium by the nephron. This project proposes four specific aims: (1) to identify and characterize the mechanism of action and functional significance of both CP-450 arachidonate metabolites that augment renal sodium retention and those metabolites that inhibit renal sodium reabsorption; (2) to test the hypothesis that cross-metabolism, i.e., metabolism of arachidonate by both the CP-450 pathway and the cyclooxygenase pathway, yields important biologically active metabolites which modify sodium transport by activating specific prostaglandin receptor sub-types; (3) to test the hypothesis that the proximal tubule and collecting duct serve as important sites for arachidonate cross- metabolism within the kidney; (4) to characterize the urinary excretion of CP-450 arachidonate metabolites in normal humans, normal humans on varying salt intake, patients with essential hypertension, and pregnant females with and without pregnancy-induced hypertension. These studies, in concert with the multi-discipline approach in this Program Project Grant, will define the importance of cytochrome P-450 arachidonate metabolism in the regulation of normal renal function and in alterations of renal function, that produce or result from hypertension.

现在很清楚，某些花生四烯酸代谢物源自 细胞色素 P-450 (CP-450) 代谢对离子和 哺乳动物肾脏中的水运输。 目前尚不清楚 是该途径的生理学和病理生理学重要性 调节肾脏对盐和水平衡的贡献。 那里 然而，有一些令人信服的观察结果需要 彻底分析 CP-450 花生四烯酸的功能意义 肾脏调节钠重吸收的代谢。 这些 观察结果基本上来自实验性高血压模型。 在 自发性高血压大鼠 (SHR)，McGiff、Schwartzman、Abraham 和他们的同事暗示了 omega 和 omega-1 的作用 花生四烯酸的羟基化在高血压的发展中。 然而，功能联系仍不清楚。 在我们的研究中 组，似乎饮食盐负荷显着诱导环氧化酶 在正常大鼠中具有活性，但在达尔盐敏感遗传大鼠中没有活性 大鼠品系。 再次，达尔盐敏感的功能链接 动物尚未阐明。 尽管高血压动物的数据 模型为研究钠的调节提供了主要动力 通过细胞色素 P-450 代谢物运输，我们相信这些 化合物将在钠的正常处理中发挥重要作用 由肾单位。 该项目提出了四个具体目标：（1） 识别并描述作用机制和功能 两种 CP-450 花生四烯酸代谢物增强肾功能的重要性 钠潴留和那些抑制肾钠的代谢物 重吸收； (2) 检验交叉代谢的假设，即 花生四烯酸通过 CP-450 途径和 环氧合酶途径，产生重要的生物活性代谢物 通过激活特定的前列腺素来改变钠的转运 受体亚型； (3) 检验近曲小管的假设 和集合管是花生四烯酸交叉的重要场所 肾脏内的新陈代谢； (4)表征尿排泄 正常人体内的 CP-450 花生四烯酸代谢物，正常人 不同盐摄入量、原发性高血压患者和孕妇 有或没有妊娠高血压的女性。 这些研究， 与本计划项目中的多学科方法相一致 格兰特将定义细胞色素 P-450 花生四烯酸的重要性 正常肾功能调节和改变中的代谢 肾功能，产生或导致高血压。