Effect of Cytochrome P450 Metabolites of Arachidonic Acid in Nephrology

Abstract

Thirty-five years ago, a third pathway for the metabolism of arachidonic acid by cytochrome P450 enzymes emerged. Subsequent work revealed that 20-hydroxyeicosatetraenoic and epoxyeicosatrienoic acids formed by these pathways have essential roles in the regulation of renal tubular and vascular function. Sequence variants in the genes that produce 20-hydroxyeicosatetraenoic acid are associated with hypertension in humans, whereas the evidence supporting a role for variants in the genes that alter levels of epoxyeicosatrienoic acids is less convincing. Studies in animal models suggest that changes in the production of cytochrome P450 eicosanoids alter BP. However, the mechanisms involved remain controversial, especially for 20-hydroxyeicosatetraenoic acid, which has both vasoconstrictive and natriuretic actions. Epoxyeicosatrienoic acids are vasodilators with anti-inflammatory properties that oppose the development of hypertension and CKD; 20-hydroxyeicosatetraenoic acid levels are elevated after renal ischemia and may protect against injury. Levels of this eicosanoid are also elevated in polycystic kidney disease and may contribute to cyst formation. Our review summarizes the emerging evidence that cytochrome P450 eicosanoids have a role in the pathogenesis of hypertension, polycystic kidney disease, AKI, and CKD.

Keywords: acute renal failure; chronic kidney disease; glomerular disease; hypertension; polycystic kidney disease.

Figure 1.

CYP450 pathways for the formation of 20-HETE and EETs. AA esterified into membrane phospholipids is released via cytoplasmic phospholipase A2 (cPLA2) after membrane stretch or through the action of hormones and autacoids. Free AA is metabolized via CYP450 enzymes of the CYP2C and CYP2J families to EETs and by CYP4A or CYP4F enzymes to 20-HETE. EETs are hydrolyzed to dihydroxyeicosatrienoic acids (DHETs) by sEH. 20-HETE is metabolized to shorter-chain carboxylic acids by alcohol dehydrogenase (ADH) and β-oxidation, by COX2 to 20-hydroxy-PG, and by 12-lipoxygenase (12-LOX) to 12,20-hydroxy-eicosatrienoic acid. It also can be conjugated by uridine glucuronosyltransferase (UGT), filtered, and excreted in the urine.

Figure 2.

Renal and vascular actions of 20-HETE and EETs. 20-HETE and EETs are formed in the kidney and renal and peripheral arterioles. The positive and negative modulatory effects of EETs and 20-HETE on various aspects of vascular and renal function are indicated by up and down arrows. IR, ischemia-reperfusion; RBF, renal blood flow; TGF, tubuloglomerular feedback.

Figure 3.

Role of 20-HETE and EETs in hypertension. The renal and vascular production of 20-HETE is altered in various genetic and experimental rodent models of hypertension and CYP4A, CYP4F, and CYP2C transgenic and knockout (KO) mouse models. Models associated with decreases in the formation of EETs and 20-HETE are indicated in blue and green, respectively, and those associated with increases are indicated in black. Elevations in the vascular formation of 20-HETE increase renal and peripheral vascular resistance and produce salt-insensitive forms of hypertension, whereas decreases in the formation of 20-HETE and EETs increase sodium transport and promote salt-sensitive hypertension. DHT, dihydrotestosterone; ET1, endothelin 1; L-NAME, N(ω)-nitro-L-arginine methyl ester.