Cytochrome<i>P</i>-450 4A isoform expression and 20-HETE synthesis in renal preglomerular arteries

Marji, Jackleen; Wang, Mong Heng; Laniado−Schwartzman, Michal

doi:10.1152/ajprenal.00265.2001

Cited by 66 publications

(80 citation statements)

References 31 publications

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“…Early studies in the SHR suggested that an increase in vascular-derived 20-HETE acts to enhance preglomerular vascular tone, which leads to resetting of the pressure-natriuretic response and the development of hypertension. 13,14 This hypothesis is consistent with the observations that acute treatment of SHR with ABT, an inhibitor of 20-HETE production, or antisense oligonucleotides directed against the Cyp4a1 isoform is able to decrease vascular reactivity and lower blood pressure. 15,16 However, the results of other studies indicating that the induction of the renal production of 20-HETE with fibrates reduces blood pressure in the SHR have suggested an opposing role for tubular derived 20-HETE in the regulation of blood pressure in this model.…”

Section: Discussionsupporting

confidence: 86%

Fenofibrate Prevents the Development of Angiotensin II–Dependent Hypertension in Mice

et al. 2005

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Abstract-Previous studies have indicated that the production of 20-hydroxyecisatatraenoic acid (20-HETE) is similar in the liver of C57/B6 mice and rats, but the renal production of 20-HETE is very low in this strain of mice. The present study examined the effects of induction of the renal production of 20-HETE with fenofibrate (FF) on the development of angiotensin II (Ang II)-dependent hypertension in C57BL/6J mice. The mice were divided into 4 groups and treated with vehicle (control), FF (90 mg/kg per day, IP), Ang II (1000 ng/kg per minute, SC), and Ang II plus FF. Mean arterial blood pressure (MAP) averaged 109Ϯ4 and 106Ϯ2 mm Hg in control and FF-treated mice (nϭ7). MAP was significantly increased in the Ang II-treated mice to 144Ϯ4 mm Hg (nϭ7). However, FF treatment prevented the development of Ang II-dependent hypertension, with MAP averaging 115Ϯ5 mm Hg in mice treated with both Ang II plus FF (nϭ7). Renal production of 20-HETE was very low in control (nϭ7) and Ang II-treated (nϭ7) mice and was increased by Ͼ2-fold in FF-treated (nϭ7) and Ang II plus FF-treated (nϭ7) mice. The levels of Cyp4A proteins were markedly increased in the kidneys of mice treated with FF and Ang II plus FF but not in the renal vasculature. These results suggest that upregulation of the production of 20-HETE in renal tubules may contribute to the blood pressure-lowering effects of FF treatment in Ang II-dependent hypertension in C57BL/6J mice. 1 Of these metabolites, 20-hydroxyecisatatraenoic acid (20-HETE) has been reported to inhibit sodium transport and promote natriuresis. 2,3 Studies in Dahl salt-sensitive (Dahl S) rats indicate that production of 20-HETE in the outer medulla is reduced and that this defect contributes to the development of salt-sensitive hypertension in this model. 4,5 Induction of the renal expression of Cyp4a enzymes in the kidney using fibrate compounds has been reported to lower blood pressure in spontaneously hypertensive rats (SHR) and stroke-prone SHR and Dahl S rats. 6,7 The reduction of blood pressure with clofibrate in Dahl S rats was also associated with the normalization of the pressurenatruretic response in this model. 8 In mice, the expression of Cyp4A proteins and renal 20-HETE production is reduced during the development of deoxycorticosterone acetate-salt hypertension. 9 Induction of the renal production of 20-HETE with bezafibrate lowered the blood pressure and improved renal hemodynamics in this model. 10 These studies suggest that a deficiency in the renal production of 20-HETE may promote the development of hypertension. More recently, we have reported that the renal production of 20-HETE is also very low in the kidney of C57BL/6J mice, 11 indicating that they may be a good model to determine the role of CYP metabolites of AA in the regulation of renal function and blood pressure. Thus, the present study examined the effects of induction of the renal production of 20-HETE with FF on the development of Ang II-dependent hypertension in C57BL/6J mice.

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Section: Discussionsupporting

confidence: 86%

Fenofibrate Prevents the Development of Angiotensin II–Dependent Hypertension in Mice

et al. 2005

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“…6,7 CYP4A proteins are present in vascular tissues and show distinct distribution along the vascular tree. 8 Suppression and overexpression of CYP4A proteins in small arteries and arterioles decreases and increases, respectively, vascular reactivity and myogenic tone 7,9,10 ; these effects can be reversed by the addition of 20-HETE or inhibition of its synthesis.…”

mentioning

confidence: 99%

Vascular Cytochrome P450 4A Expression and 20-Hydroxyeicosatetraenoic Acid Synthesis Contribute to Endothelial Dysfunction in Androgen-Induced Hypertension

et al. 2007

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Abstract-Epidemiological evidence suggests a role for sex-dependent mechanisms in the pathophysiology of hypertension. It has been shown that 5␣-dihydrotestosterone (DHT) administration (56 mg/kg of body weight per day IP for 14 days) increases blood pressure, cytochrome P450 4A expression, and 20-hydroxyeicosatetraenoic acid synthesis in rats.We examined whether increased vascular 20-hydroxyeicosatetraenoic acid synthesis underlies endothelial dysfunction and hypertension in DHT-treated male Sprague-Dawley rats by using HET0016, a selective cytochrome P450 4A inhibitor. Coadministration of HET0016 (10 mg/kg per day IP for 14 days) to DHT-treated rats markedly reduced DHT-induced interlobar arterial production of 20-hydroxyeicosatetraenoic acid (14.3Ϯ1.5 versus 1.5Ϯ0.5 ng/mg of protein per hour; PϽ0.05), superoxide anion (246Ϯ47 versus 31Ϯ8 cpm/g of protein), and the levels of gp91-phox, p47-phox, and 3-nitrosylated proteins. Moreover, the maximal relaxing response to acetylcholine in phenylephrinepreconstricted renal interlobar arteries from DHT-treated rats (42.8Ϯ4.8%) significantly (PϽ0.05) increased in the presence of HET0016 (81.5Ϯ10.8%). Importantly, the administration of HET0016 negated DHT-induced hypertension; systolic blood pressure was reduced from 146Ϯ2 mm Hg in DHT-treated rats to 130Ϯ1 mm Hg ( The synthesis of 20-HETE is catalyzed primarily by enzymes of the cytochrome P450 (CYP) 4A family. 6,7 CYP4A proteins are present in vascular tissues and show distinct distribution along the vascular tree. 8 Suppression and overexpression of CYP4A proteins in small arteries and arterioles decreases and increases, respectively, vascular reactivity and myogenic tone 7,9,10 ; these effects can be reversed by the addition of 20-HETE or inhibition of its synthesis.CYP4A and 20-HETE synthesis have been linked to hypertension in numerous experimental models. In the spontaneously hypertensive rat, depletion or inhibition of CYP4A activity lowers blood pressure (BP). 11,12 Inhibition of vascular 20-HETE synthesis by intravenous administration of CYP4A1 or CYP4A2 antisense oligonucleotides decreases BP in normotensive and hypertensive rats, 6,7 whereas transduction with adenoviruses expressing the CYP4A2 protein increases vascular CYP4A expression and 20-HETE levels and augments BP. 13 A role for androgens in promoting elevation of BP is well recognized 14 and, according to recent studies, such a role may rely on increased synthesis of vascular 20-HETE. Hence, mice deficient in cyp4a14 (the mouse homologue of CYP4A2) displayed androgen-sensitive hypertension, which was reversed by castration. 15 In these mice, cyp4a12 expression (the mouse homologue of CYP4A8) is elevated and so is renal microsomal 20-HETE synthesis. Similarly, androgeninduced hypertension in rats treated with 5␣-dihydrotestosterone (DHT) has been associated with increased CYP4A8 expression and renal vascular 20-HETE synthesis. 16 The mechanisms by which 20-HETE promotes hypertension are primarily linked to its ability to sensitize constrictor responsi...

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“…Four CYP4A isoforms (CYP4A1, CYP4A2, CYP4A3, and CYP4A8) are expressed in the kidney of rats, and these isoforms are able to catalyze the hydroxylation of fatty acids and produce 20-HETE. 14 Salt sensitivity is the causative agent for an important subgroup of humans with essential hypertension. 11 Considerable evidence suggests that endothelial dysfunction is linked to end-organ damage in human salt-sensitive hypertension.…”

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confidence: 99%

Decreased Renal Cytochrome P450 2C Enzymes and Impaired Vasodilation Are Associated With Angiotensin Salt-Sensitive Hypertension

et al. 2003

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Abstract-Excess dietary salt intake differentially modulates the activity of cytochrome (CYP) P450 enzymes in kidney cortex. Exactly how increased angiotensin (Ang) II levels and hypertension change the regulatory effect of high salt on CYP450 enzymes remains unclear. The present study investigated the effects of combined administration of Ang II and a high-salt diet on P450 epoxygenase and hydroxylase protein levels in kidney, as well as afferent arteriolar responses to acetylcholine and sodium nitroprusside. High dietary salt administration for 14 days resulted in increased renal cortical CYP2C11 protein levels, and a significant increase of CYP2C11 and CYP2C23 protein levels in renal microvessels. Administration of Ang II in combination with a high-salt diet prevented the upregulation of renal cortical CYP2C11 protein expression observed with high dietary salt alone, and significantly downregulated expression of CYP2C11, CYP2C23, and CYP2J protein in renal microvessels. A high-salt diet alone decreased CYP4A protein in kidney cortex, and renal cortical CYP4A protein level remained at a low level in Ang II-infused rats treated with a high-salt diet. Increases in blood pressure during Ang II infusion were greater in rats fed a high-salt diet. In addition, afferent arteriolar responsiveness to acetylcholine and sodium nitroprusside was significantly attenuated in Ang II-treated rats versus controls. This decrease was significantly enhanced in Ang II-treated rats given a high-salt diet. These results support the hypothesis that an inability to upregulate CYP2C and maintain CYP2J in the rat kidney and impaired afferent arteriolar vasodilation with chronic Ang II infusion contribute to salt-induced elevation of arterial pressure.

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CytochromeP-450 4A isoform expression and 20-HETE synthesis in renal preglomerular arteries

Cited by 66 publications

References 31 publications

Fenofibrate Prevents the Development of Angiotensin II–Dependent Hypertension in Mice

Fenofibrate Prevents the Development of Angiotensin II–Dependent Hypertension in Mice

Vascular Cytochrome P450 4A Expression and 20-Hydroxyeicosatetraenoic Acid Synthesis Contribute to Endothelial Dysfunction in Androgen-Induced Hypertension

Decreased Renal Cytochrome P450 2C Enzymes and Impaired Vasodilation Are Associated With Angiotensin Salt-Sensitive Hypertension

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