New group of lipid mediators containing omega-hydroxyarachadonic acid (20-HETE).

Abstract

20-HETE is a biologically active product of arachidonic acid and cytochrome P450 ω-hydroxylase of the 4A gene family and is an abundant microsomal eicosanoid in the rat kidney.1 However, very little is known about factors controlling the biosynthesis and metabolic fate of 20-HETE in the kidney. Cyclooxygenase metabolizes 20-HETE into ω-OH-PGs, formation of which was proposed to explain the vasoconstrictor activity of 20-HETE in the kidney.2 Human platelets metabolize 20-HETE into a complex mixture of products of which 11,20-dihydroxyeicosatetraenoic acid (11,20-DiHETE), and 12,20-DiHETE are the major metabolites.3. We observed that the stimulation of the rat kidney with hormones or calcium ionophore results in an accumulation of 20-HETE, which is readily detectable by GC/MS.4, 5 The release of 20-HETE from renal slices stimulated by calcium ionophore cannot be inhibited with ETYA, which suggested to us that calcium influx is required for the release of 20-HETE. The isolated perfused kidney, challenged with angiotensin II (ang II) or endothelin-1, rapidly releases 20-HETE and often other CYP450 subterminal HETEs, into the perfusion fluid in amounts 5 to 10-fold higher relative to control levels. Brief stimulation of mTAL cells with ang II leads to a selective release of 20-HETE.6 These results suggested that 20-HETE could be released from renal tissue phospholipids via a receptor-mediated activation of phospholipase (PL)A2. In this study we obtained evidence that the release of 20-HETE from renal phospholipids is possible and represents a new component of ang II-dependent effects on renal function.