Study Title:
20-HETE and Kidney Function
Study Abstract
Recent studies indicate that in the kidney arachidonic acid (AA) is metabolized by cytochrome P450 (CYP450) enzymes to produce epoxyeicosatrienoic acids (EETs), dihydroxyeicosatetraenoic acids (DiHETEs), and 19‐ and 20‐hydroxyeicosatetrienoic acids (19‐ and 20‐HETE). CYP450 metabolites of AA play a major role in the regulation of renal vascular tone, tubuloglomerular feedback (TGF), and sodium transport [1,2]. Enzymes of the CYP450 4A and 4F families catalyse the formation of 20‐HETE. CYP450 4A mRNA and protein are expressed in the renal arterioles, glomerulus, proximal tubule (PT), cortical and medullary thick ascending limb of the loop of Henle (TALH), and in the pericytes surrounding vasa recta capillaries [2,3]. The renal arterioles, PTs, and glomeruli avidly produce 20‐HETE, EETs, and DiHETEs when incubated with AA, while in the TALH, 20‐HETE is the primary metabolite of AA [2].
Enzymes of the CYP450 1A, 2B, 2C, 2D 2E, and 2J families catalyse the formation of EETs [1,4]. In the kidney, protein for each of these enzymes is expressed; however, the specific enzymes primarily responsible for EETs production in different nephron segments have not been determined.
Numerous factors influence the expression of CYP450 enzymes. High levels of CYP450 4A1 and 4A3 mRNA and protein are detected in neonatal rat kidney, but the levels of these enzymes diminish into adulthood [5,6]. In contrast, CYP450 4A2 protein is the major isoform expressed in the adult rat kidney [5,6]. In PT cells, angiotensin II (Ang II) stimulates formation of EETs [7], whereas epidermal growth factor [8], dopamine [9], and parathyroid hormone (PTH) [10] stimulate the formation of 20‐HETE. Vasopressin, Ang II, bradykinin, and calcium stimulate 20‐HETE formation in the TALH [2,4]. The expression of CYP450 4A protein is downregulated in the kidney and renal vasculature when rats are fed a high salt diet [11–13] and this can be prevented when circulating Ang II concentrations are maintained at normal levels via an i.v. infusion of Ang II [2]. On the other hand, EETs formation has been reported to be elevated by increased dietary salt intake in some strains of rats [13–15]. Upregulated epoxygenase activity has been postulated to play a role in the chronic adaptation of animals to elevations in salt intake by enhancing sodium excretion.
Renal CYP450 4A activity is increased by mineralocorticoids, glucocorticoids, and progesterone [2]. Antilipidaemic agents like clofibrate induce the expression of CYP450 4A1 and 4A3 protein and increase the formation of 20‐HETE in the kidney. A variety of vasoconstrictor agents, including Ang II, norepinephrine, vasopressin, and endothelin, stimulate phospholipases and increase 20‐HETE formation in the kidney and peripheral vasculature [4]. In contrast, NO inhibits the formation of EETs and 20‐HETE [16].
The expression of CYP450 4A enzymes in the kidney is altered in diabetes, pregnancy, hepatorenal syndrome, cyclosporin‐induced nephrotoxicity, alcohol‐induced liver disease, and in various animal models of hypertension [2]. However, the role that 20‐HETE plays in mediating the changes in renal function associated with these conditions has not yet been defined. In rats, enzymes of the CYP450 4A and 2C families exhibit sexual dimorphism [17], but the physiological significance of this observation remains unknown.
Enzymes of the CYP450 1A, 2B, 2C, 2D 2E, and 2J families catalyse the formation of EETs [1,4]. In the kidney, protein for each of these enzymes is expressed; however, the specific enzymes primarily responsible for EETs production in different nephron segments have not been determined.
Numerous factors influence the expression of CYP450 enzymes. High levels of CYP450 4A1 and 4A3 mRNA and protein are detected in neonatal rat kidney, but the levels of these enzymes diminish into adulthood [5,6]. In contrast, CYP450 4A2 protein is the major isoform expressed in the adult rat kidney [5,6]. In PT cells, angiotensin II (Ang II) stimulates formation of EETs [7], whereas epidermal growth factor [8], dopamine [9], and parathyroid hormone (PTH) [10] stimulate the formation of 20‐HETE. Vasopressin, Ang II, bradykinin, and calcium stimulate 20‐HETE formation in the TALH [2,4]. The expression of CYP450 4A protein is downregulated in the kidney and renal vasculature when rats are fed a high salt diet [11–13] and this can be prevented when circulating Ang II concentrations are maintained at normal levels via an i.v. infusion of Ang II [2]. On the other hand, EETs formation has been reported to be elevated by increased dietary salt intake in some strains of rats [13–15]. Upregulated epoxygenase activity has been postulated to play a role in the chronic adaptation of animals to elevations in salt intake by enhancing sodium excretion.
Renal CYP450 4A activity is increased by mineralocorticoids, glucocorticoids, and progesterone [2]. Antilipidaemic agents like clofibrate induce the expression of CYP450 4A1 and 4A3 protein and increase the formation of 20‐HETE in the kidney. A variety of vasoconstrictor agents, including Ang II, norepinephrine, vasopressin, and endothelin, stimulate phospholipases and increase 20‐HETE formation in the kidney and peripheral vasculature [4]. In contrast, NO inhibits the formation of EETs and 20‐HETE [16].
The expression of CYP450 4A enzymes in the kidney is altered in diabetes, pregnancy, hepatorenal syndrome, cyclosporin‐induced nephrotoxicity, alcohol‐induced liver disease, and in various animal models of hypertension [2]. However, the role that 20‐HETE plays in mediating the changes in renal function associated with these conditions has not yet been defined. In rats, enzymes of the CYP450 4A and 2C families exhibit sexual dimorphism [17], but the physiological significance of this observation remains unknown.
Study Information
Kimberly M. Hoagland, Kristopher G. Maier, Carol Moreno, Ming Yu and Richard J. Roman
Cytochrome P450 metabolites of arachidonic acid: novel regulators of renal function
Nephrol. Dial. Transplant.
2001 September
Department of Physiology, Medical College of Wisconsin, Milwaukee, USA
Full Study
