Renal cytochrome P450 ω-hydroxylase and epoxygenase activity are differentially modified by nitric oxide and sodium chloride

Oyekan, Adebayo; Youseff, T.; Fulton, David; Quilley, John; McGiff, John C.

doi:10.1172/jci6786

Cited by 99 publications

(136 citation statements)

References 38 publications

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“…These results are consistent with previous reports showing that the renal formation of 20-HETE either did not change or fell when Lewis, BrownNorway, SD, DR, and DS rats are fed a high salt diet. 22,[25][26][27][28] Together, these findings indicate that 20-HETE in the kidney plays an important role in the chronic regulation of Na ϩ excretion and blood pressure, but elevations in renal 20-HETE production per se do not contribute to the inhibition of Na ϩ transport associated with elevations in salt intake.…”

Section: Discussionmentioning

confidence: 84%

Inhibitors of 20-HETE Formation Promote Salt-Sensitive Hypertension in Rats

2003

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Abstract-This study examined whether chronic blockade of epoxyeicosatrienoic acids (EETs) and/or 20-hydroxyeicosatetraenoic acid (20-HETE) formation promotes development of salt-sensitive hypertension. Changes in blood pressure, renal cytochrome P450 metabolism of arachidonic acid, and 20-HETE excretion in response to a high salt diet were measured in rats chronically treated with 1-aminobenzotriazole (ABT, 50 mg/kg per day) to block EETs and 20-HETE formation or N-hydroxy-NЈ-(4-butyl-2 methylphenyl) formamidine (HET0016, 10 mg/kg per day) that selectively reduces 20-HETE formation. ABT reduced blood pressure in rats fed a low salt (0.4% NaCl) diet, but blood pressure rose by 20 mm Hg after these rats were switched to a high salt (8% NaCl) diet for 10 days. HET0016 had no effect on blood pressure in rats fed a low salt diet; however, blood pressure rose by 18 mm Hg after the rats were fed a high salt diet. 20-HETE formation in kidney homogenates rose by 30% and epoxygenase activity doubled when rats were fed a high salt diet. Chronic treatment with ABT and HET0016 inhibited the renal formation of 20-HETE by Ϸ90%. Renal epoxygenase activity decreased by 76% in ABT-treated rats and was not significantly altered in rats treated with HET0016. 20-HETE excretion rose from 470Ϯ21 to 570Ϯ41 ng/d when the rats were switched from the low to the high salt diet. 20-HETE excretion fell by 68% and 85% in rats that were chronically treated with ABT and HET0016. These results suggest that chronic blockade of the formation of 20-HETE promotes the development of salt-sensitive hypertension in rats. Key Words: rats, Dahl Ⅲ metabolism Ⅲ arachidonic acids Ⅲ blood pressure Ⅲ hypertension, sodium-dependent T he role of the cytochrome P450 (P450) metabolites of arachidonic acid (AA) in the development and maintenance of hypertension remains uncertain in part because this pathway has both prohypertensive and antihypertensive actions. 1 20-Hydroxyeicosatetraenoic acid (20-HETE) inhibits Na ϩ transport in the proximal tubule and thick ascending limb of the loop of Henle (TALH), 2-5 and compounds that induce the renal formation of 20-HETE lower blood pressure in Dahl salt-sensitive (DS) rats. 1 Similarly, epoxyeicosatrienoic acids (EETs) inhibit Na ϩ transport in the proximal tubule and collecting duct, 6,7 and increasing the renal levels of EETs with inhibitors of soluble epoxide hydrolase (sEH) reduces blood pressure in spontaneously hypertensive rats (SHRs) 8 and angiotensin II-induced hypertensive rats. 9 However, 20-HETE is also a potent vasoconstrictor, 1 and many investigators have reported that blocking the vascular effects of 20-HETE may contribute to its antihypertensive effect in SHR and other experimental models of hypertension. 10,11 Part of the problem in defining the role of the P450 metabolites of AA in the control of blood pressure has been the lack of selective inhibitors of the pathway that chronically block the formation of 20-HETE and EETs in vivo. Inhibitors that are commonly used to inhibit the formation of EETs and ...

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Section: Discussionmentioning

confidence: 84%

Inhibitors of 20-HETE Formation Promote Salt-Sensitive Hypertension in Rats

2003

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“…11,15 CYP2C isoforms are considered the major renal arachidonic acid epoxygenases in the kidney. In particular, CYP2C23 is highly expressed in rat kidney, where it exerts an important role in regulating EET formation.…”

Section: Discussionmentioning

confidence: 99%

“…15,16 In contrast, the expression of CYP2C11 and CYP2C23 and the formation of EETs in the kidney are increased by a high-salt diet. 11,15 Although studies in Sprague-Dawley rats suggest that a salt-inducible renal epoxygenase has antihypertensive properties, kidney EET production is inappropriately low during the development of salt-sensitive hypertension. 17 There are many CYP450 isoforms, expressed in the kidney, that produce EETs; however, little is known about which of these isoforms are regulated in the renal microvessels and about their involvement in the development of angiotensin salt-sensitive hypertension.…”

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confidence: 99%

“…Studies have revealed that renal CYP450 -hydroxylase and epoxygenase activity are differentially modified by sodium chloride. 15 High dietary salt downregulates the expression of CYP4A protein in the kidney and renal vaculature. 15,16 In contrast, the expression of CYP2C11 and CYP2C23 and the formation of EETs in the kidney are increased by a high-salt diet.…”

mentioning

confidence: 99%

“…15 High dietary salt downregulates the expression of CYP4A protein in the kidney and renal vaculature. 15,16 In contrast, the expression of CYP2C11 and CYP2C23 and the formation of EETs in the kidney are increased by a high-salt diet. 11,15 Although studies in Sprague-Dawley rats suggest that a salt-inducible renal epoxygenase has antihypertensive properties, kidney EET production is inappropriately low during the development of salt-sensitive hypertension.…”

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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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Inhibition of Cytochrome P450 Enzymes

Correia

Hollenberg

2015

Cytochrome P450

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Renal cytochrome P450 ω-hydroxylase and epoxygenase activity are differentially modified by nitric oxide and sodium chloride

Cited by 99 publications

References 38 publications

Inhibitors of 20-HETE Formation Promote Salt-Sensitive Hypertension in Rats

Inhibitors of 20-HETE Formation Promote Salt-Sensitive Hypertension in Rats

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

Inhibition of Cytochrome P450 Enzymes

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