20-HETE and the kidney: resolution of old problems and new beginnings

The protean properties of 20-hydroxyeicosatetraenoic acid (HETE), vasoactiv ity, mitogenicity, and modulation of transport in key nephron segments, ser ve as the basis for the essential roles of 20-HETE in the regulation of the renal circulation and electrolyte excretion and as a second messenger for endothelin-1 and mediator of selective renal effects of ANG II. Renal autor egulation and tubular glomerular feedback are mediated by 20-HETE through c onstriction of preglomerular arterioles, responses that are maintained by 2 0-HETE inhibition of calcium-activated potassium channels. 20-HETE modulate s ion transport in the proximal tubules and the thick ascending limb by aff ecting the activities of Na+-K+-ATPase and the Na+-K+-2Cl(-) cotransporter, respectively. The range and diversity of activity of 20-HETE derives in la rge measure from COX-dependent transformation of 20-HETE to products affect ing vasomotion and salt and water excretion. Nitric oxide (NO) exerts a neg ative modulatory effect on 20-HETE formation; inhibition of NO synthesis pr oduces marked perturbation of renal function resulting from increased 20-HE TE production. 20-HETE is an essential component of interactions involving several hormonal systems that have central roles in blood pressure homeosta sis, including angiotensins, endothelins, NO, and cytokines. 20-HETE is the preeminent renal eicosanoid, overshadowing PGE(2) and PGI(2). This review is intended to provide evidence for the physiological roles for cytochrome P-450-derived eicosanoids, particularly 20-HETE, and seeks to extend this k nowledge to a conceptual framework for overall cardiovascular function.