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

现在很明显，某些花生四烯酸代谢产物源于 细胞色素P-450(CP-450)代谢对离子和蛋白质有重要影响 哺乳动物肾脏中的水运输。目前还不太清楚的是 这一途径的生理学和病理生理学重要性在 调节肾脏对水盐平衡的贡献。那里 然而，有一些令人信服的观察结果呼吁 深入分析CP-450花生四烯酸的功能意义 肾脏对钠重吸收的调节中的代谢。这些 观察结果基本上来自实验性高血压模型。在……里面 自发性高血压大鼠(SHR)，McGiff，Schwartzman，Abraham 他们的同事发现了omega和omega-1的作用。 花生四烯酸羟化在高血压发病中的作用。 然而，功能上的联系仍不清楚。在我们的研究中 一组，似乎饮食盐负荷显著诱导环氧合酶 正常大鼠的活性，但不是Dahl盐敏感基因的活性 品系的老鼠。再一次，Dahl对盐敏感的功能环节 动物还没有被阐明。尽管高血压动物的数据 模型为研究钠的调节提供了主要的动力 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 在肾单位旁边。本项目提出了四个具体目标：(1) 确定并描述其作用和功能的机制 CP-450花生四烯酸代谢产物在补肾作用中的意义 钠滞留和抑制肾钠的代谢物 重吸收；(2)检验交叉新陈代谢，即， 花生四烯酸代谢的CP-450途径和 环氧合酶途径，产生重要的生物活性代谢物 它们通过激活特定的前列腺素来改变钠的转运 受体亚型；(3)检验假设近端小管 收集管是花生四氢叶甲交配的重要部位。 肾内代谢；(4)表征尿液排泄 CP-450花生四烯酸代谢产物在正常人体内的分布 不同的盐摄入量，高血压患者和孕妇 患有和不患有妊娠高血压综合征的女性。这些研究， 与本计划项目中的多学科方法协调一致 Grant，将定义细胞色素P-450花生四烯酸的重要性 代谢在调节正常肾功能和改变中的作用 由高血压产生或导致的肾功能损害。

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.