Cytochrome P450 metabolites of arachidonic acid: novel regulators of renal function

Recent studies indicate that in the kidney arachi-donic acid (AA) is metabolized by cytochrome P450(CYP450) enzymes to produce epoxyeicosatrie-noic acids (EETs), dihydroxyeicosatetraenoic acids(DiHETEs), and 19- and 20-hydroxyeicosatetrienoicacids (19- and 20-HETE). CYP450 metabolites of AAplay a major role in the regulation of renal vasculartone, tubuloglomerular feedback (TGF), and sodiumtransport w1,2x. Enzymes of the CYP450 4A and 4Ffamilies catalyse the formation of 20-HETE. CYP4504A mRNA and protein are expressed in the renalarterioles, glomerulus, proximal tubule (PT), corticaland medullary thick ascending limb of the loop ofHenle (TALH), and in the pericytes surroundingvasa recta capillaries w2,3x. The renal arterioles, PTs,and glomeruli avidly produce 20-HETE, EETs, andDiHETEs when incubated with AA, while in theTALH, 20-HETE is the primary metabolite of AA w2x.Enzymes of the CYP450 1A, 2B, 2C, 2D 2E, and2J families catalyse the formation of EETs w1,4x.Inthe kidney, protein for each of these enzymes isexpressed; however, the speciﬁc enzymes primarilyresponsible for EETs production in different nephronsegments have not been determined.Numerous factors inﬂuence the expression ofCYP450 enzymes. High levels of CYP450 4A1 and4A3 mRNA and protein are detected in neonatal ratkidney, but the levels of these enzymes diminish intoadulthood w5,6x. In contrast, CYP450 4A2 proteinis the major isoform expressed in the adult rat kidneyw5,6x. In PT cells, angiotensin II (Ang II) stimulatesformation of EETs w7x, whereas epidermal growthfactor w8x, dopamine w9x, and parathyroid hormone(PTH) w10x stimulate the formation of 20-HETE.Vasopressin, Ang II, bradykinin, and calcium stimulate20-HETE formation in the TALH w2,4x. The expres-sion of CYP450 4A protein is downregulated in thekidney and renal vasculature when rats are fed a highsalt diet w11–13x and this can be prevented whencirculating Ang II concentrations are maintained atnormal levels via an i.v. infusion of Ang II w2x. On theother hand, EETs formation has been reported to beelevated by increased dietary salt intake in some strainsof rats w13–15x. Upregulated epoxygenase activityhas been postulated to play a role in the chronicadaptation of animals to elevations in salt intake byenhancing sodium excretion.Renal CYP450 4A activity is increased by minera-locorticoids, glucocorticoids, and progesterone w2x.Antilipidaemic agents like cloﬁbrate induce the expres-sion of CYP450 4A1 and 4A3 protein and increase theformation of 20-HETE in the kidney. A variety ofvasoconstrictor agents, including Ang II, norepineph-rine, vasopressin, and endothelin, stimulate phospho-lipases and increase 20-HETE formation in the kidneyand peripheral vasculature w4x. In contrast, NO inhibitsthe formation of EETs and 20-HETE w16x.The expression of CYP450 4A enzymes in the kidneyis altered in diabetes, pregnancy, hepatorenal syn-drome, cyclosporin-induced nephrotoxicity, alcohol-induced liver disease, and in various animal models ofhypertension w2x. However, the role that 20-HETEplays in mediating the changes in renal function asso-ciated with these conditions has not yet been deﬁned.In rats, enzymes of the CYP450 4A and 2C familiesexhibit sexual dimorphism w17x, but the physiologicalsigniﬁcance of this observation remains unknown.