Cytochrome P450 metabolites of arachidonic acid in the control of renal function

Abstract

Recent studies indicate that arachidonic acid is primarily metabolized by cytochrome P450 enzymes of the 4A and 2C families in the kidney to 20-hydroxyeicosatetraenoic acid (HETE), epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids. These compounds play central roles in the regulation of renal tubular and vascular function. 20-HETE is produced by renal vascular smooth muscle (VSM) cells and is a potent constrictor that depolarizes VSM cells by blocking the calcium-activated potassium channel. Inhibition of the formation of 20-HETE blocks the myogenic response of isolated renal arterioles in vitro, and autoregulation of renal blood flow and tubuloglomerular feedback responses in vivo. EETs are products formed in the endothelium and are potent dilators that activate the calcium-activated potassium channel in renal VSM. Endothelial-dependent vasodilators stimulate the release of EETs, and these compounds appear to serve as an endothelial-derived hyperpolarizing factor. EETs and 20-HETE are produced in the proximal tubule. There, they regulate sodium/potassium-ATPase activity and serve as second messengers for the natriuretic effects of dopamine, parathyroid hormone and angiotensin II. 20-HETE is also produced in the thick ascending loop of Henle. It regulates sodium-potassium-chloride transport in this nephron segment. The renal production of cytochrome P450 metabolites of arachidonic acid is altered in hypertension, diabetes, toxemia of pregnancy, and hepatorenal syndrome. Given the importance of cytochrome P450 metabolites of arachidonic acid in the control of renal function, it is likely that changes in this system contribute to the abnormalities in renal function that are associated with many of these conditions.