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

CYTOCHROME P-450 花生四烯酸代谢

• 批准号: 6238924
• 负责人: Matthew Douglas Breyer
• 金额: $ 13.44万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6238924
• 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.

现在很清楚的是，某些花生四烯酸代谢物， 细胞色素P-450（CP-450）代谢对离子 哺乳动物肾脏中的水运输。 目前不太清楚的是 这条通路在生理和病理上的重要性， 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， 深入分析CP-450花生四烯酸酯的功能意义 在调节肾脏钠重吸收的代谢中起重要作用。 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 羟基化花生四烯酸在高血压的发展。 然而，功能上的联系仍然不清楚。 在我们的研究中， 组，似乎膳食盐负荷显着诱导环氧酶 活性在正常大鼠，但不是在达尔盐敏感的遗传 一种老鼠。 再次，在达尔盐敏感的功能环节， 动物没有被发现。 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代谢物的转运，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） 确定和描述作用机制和功能 两种CP-450花生四烯酸代谢物增加肾功能意义 钠潴留和那些抑制肾钠的代谢物 重吸收;（2）检验交叉代谢，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产物 其通过激活特定的前列腺素来改变钠转运 受体亚型;（3）检验近端小管 和集合管是花生四烯酸交叉的重要部位， 肾内代谢;（4）表征尿排泄 CP-450花生四烯酸代谢物在正常人、正常人 不同的盐摄入量，原发性高血压患者，孕妇 有和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，将确定细胞色素P-450花生四烯酸的重要性， 在正常肾功能的调节和改变中的代谢 指肾功能，由高血压产生或导致。