FUNCTIONAL SIGNIFICANCE OF CYTOCHROME P450 CYCLOOXYGENASE

点击翻译按钮获取中文摘要

20-hydroxyeicosatetraenoic acid (20-HETE) is the principal eicosanoid of key renal structures where it serves an essential component in the regulation of renal vascular and tubular function. In view of the importance of 20-HETE to renal function, the identification and characterization of those factors that govern production and activity of 20-HETE assume a high priority as they determine the depth and breadth of the renal actions of the eicosanoid. Cyclooxygenases (COX-1 and COX 2) and nitric oxide synthases (NOS) have been identified as being central to the regulation of 20-HETE metabolism and production, respectively. Three Aims will address the postulated importance of COX and NO to 20-HETE levels and activities in the kidney. AIM 1 makes of the AII infusion model of hypertension to determine relationship and possible interactions of cytokines, NO and COX (both-1 and -2) that affect production and biological activities of 20-HETE. Aim 2 draws upon the relatively selective effect of high salt intake on NO production and low salt intake on cortical COX-2 expression in order to study their separate effects on 20-HETE tissue levels and spectrum of biological activities of 20-HETE metabolites in the cortex. AIM 3 addresses the powerful negative effect of glucocorticoids on COX- 2 expression in the TAL in order to define interactions involving TNF and COX-2 (and possibly iNOS) post-adrenal and to relate one or more of these factors to a postulated depression of CYP450 AA metabolism and to changes in renal function.