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

A. O. Oyekan, T. Youseff, D. Fulton, J. Quilley, J. C. McGiff

Research output: Contribution to journalArticle

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Abstract

Renal function is perturbed by inhibition of nitric oxide synthase (NOS). To probe the basis of this effect, we characterized the effects of nitric oxide (NO), a known suppressor of cytochrome P450 (CYP) enzymes, on metabolism of arachidonic acid (AA), the expression of ω-hydroxylase, and the efflux of 20-hydroxyeicosatetraenoic acid (20-HETE) from the isolated kidney. The capacity to convert [14C]AA to HETEs and epoxides (EETs) was greater in cortical microsomes than in medullary microsomes. Sodium nitroprusside (10-100 μM), an NO donor, inhibited renal microsomal conversion of [14C]AA to HETEs and EETs in a dose-dependent manner. 8-bromo cGMP (100 μM), the cell-permeable analogue of cGMP, did not affect conversion of [14C]AA. Inhibition of NOS with N(ω)-nitro-L-arginine-methyl ester (L-NAME) significantly increased conversion of [14C]AA to HETE and greatly increased the expression of ω-hydroxylase protein, but this treatment had only a modest effect on epoxygenase activity. L-NAME induced a 4-fold increase in renal efflux of 20-HETE, as did L-nitroarginine. Oral treatment with 2% sodium chloride (NaCl) for 7 days increased renal epoxygehase activity, both in the cortex and the medulla. In contrast, cortical ω-hydroxylase activity was reduced by treatment with 2% NaCl. Coadministration of L-NAME and 2% NaCl decreased conversion of [14C]AA to HETES without affecting epoxygenase activity. Thus, inhibition of NOS increased ω-hydroxylase activity, CYP4A expression, and renal efflux of 20- HETE, whereas 2% NaCl stimulated epoxygenase activity.

Original languageEnglish (US)
Pages (from-to)1131-1137
Number of pages7
JournalJournal of Clinical Investigation
Volume104
Issue number8
DOIs
StatePublished - Oct 1999
Externally publishedYes

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Mixed Function Oxygenases
Arachidonic Acid
Sodium Chloride
Cytochrome P-450 Enzyme System
Nitric Oxide
Kidney
Hydroxyeicosatetraenoic Acids
NG-Nitroarginine Methyl Ester
Nitric Oxide Synthase
Microsomes
Cytochrome P-450 CYP4A
Nitric Oxide Donors
Nitroarginine
Epoxy Compounds
Nitroprusside
20-hydroxy-5,8,11,14-eicosatetraenoic acid
Proteins

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Renal cytochrome P450 ω-hydroxylase and epoxygenase activity are differentially modified by nitric oxide and sodium chloride. / Oyekan, A. O.; Youseff, T.; Fulton, D.; Quilley, J.; McGiff, J. C.

In: Journal of Clinical Investigation, Vol. 104, No. 8, 10.1999, p. 1131-1137.

Research output: Contribution to journalArticle

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abstract = "Renal function is perturbed by inhibition of nitric oxide synthase (NOS). To probe the basis of this effect, we characterized the effects of nitric oxide (NO), a known suppressor of cytochrome P450 (CYP) enzymes, on metabolism of arachidonic acid (AA), the expression of ω-hydroxylase, and the efflux of 20-hydroxyeicosatetraenoic acid (20-HETE) from the isolated kidney. The capacity to convert [14C]AA to HETEs and epoxides (EETs) was greater in cortical microsomes than in medullary microsomes. Sodium nitroprusside (10-100 μM), an NO donor, inhibited renal microsomal conversion of [14C]AA to HETEs and EETs in a dose-dependent manner. 8-bromo cGMP (100 μM), the cell-permeable analogue of cGMP, did not affect conversion of [14C]AA. Inhibition of NOS with N(ω)-nitro-L-arginine-methyl ester (L-NAME) significantly increased conversion of [14C]AA to HETE and greatly increased the expression of ω-hydroxylase protein, but this treatment had only a modest effect on epoxygenase activity. L-NAME induced a 4-fold increase in renal efflux of 20-HETE, as did L-nitroarginine. Oral treatment with 2{\%} sodium chloride (NaCl) for 7 days increased renal epoxygehase activity, both in the cortex and the medulla. In contrast, cortical ω-hydroxylase activity was reduced by treatment with 2{\%} NaCl. Coadministration of L-NAME and 2{\%} NaCl decreased conversion of [14C]AA to HETES without affecting epoxygenase activity. Thus, inhibition of NOS increased ω-hydroxylase activity, CYP4A expression, and renal efflux of 20- HETE, whereas 2{\%} NaCl stimulated epoxygenase activity.",
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T1 - Renal cytochrome P450 ω-hydroxylase and epoxygenase activity are differentially modified by nitric oxide and sodium chloride

AU - Oyekan, A. O.

AU - Youseff, T.

AU - Fulton, D.

AU - Quilley, J.

AU - McGiff, J. C.

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N2 - Renal function is perturbed by inhibition of nitric oxide synthase (NOS). To probe the basis of this effect, we characterized the effects of nitric oxide (NO), a known suppressor of cytochrome P450 (CYP) enzymes, on metabolism of arachidonic acid (AA), the expression of ω-hydroxylase, and the efflux of 20-hydroxyeicosatetraenoic acid (20-HETE) from the isolated kidney. The capacity to convert [14C]AA to HETEs and epoxides (EETs) was greater in cortical microsomes than in medullary microsomes. Sodium nitroprusside (10-100 μM), an NO donor, inhibited renal microsomal conversion of [14C]AA to HETEs and EETs in a dose-dependent manner. 8-bromo cGMP (100 μM), the cell-permeable analogue of cGMP, did not affect conversion of [14C]AA. Inhibition of NOS with N(ω)-nitro-L-arginine-methyl ester (L-NAME) significantly increased conversion of [14C]AA to HETE and greatly increased the expression of ω-hydroxylase protein, but this treatment had only a modest effect on epoxygenase activity. L-NAME induced a 4-fold increase in renal efflux of 20-HETE, as did L-nitroarginine. Oral treatment with 2% sodium chloride (NaCl) for 7 days increased renal epoxygehase activity, both in the cortex and the medulla. In contrast, cortical ω-hydroxylase activity was reduced by treatment with 2% NaCl. Coadministration of L-NAME and 2% NaCl decreased conversion of [14C]AA to HETES without affecting epoxygenase activity. Thus, inhibition of NOS increased ω-hydroxylase activity, CYP4A expression, and renal efflux of 20- HETE, whereas 2% NaCl stimulated epoxygenase activity.

AB - Renal function is perturbed by inhibition of nitric oxide synthase (NOS). To probe the basis of this effect, we characterized the effects of nitric oxide (NO), a known suppressor of cytochrome P450 (CYP) enzymes, on metabolism of arachidonic acid (AA), the expression of ω-hydroxylase, and the efflux of 20-hydroxyeicosatetraenoic acid (20-HETE) from the isolated kidney. The capacity to convert [14C]AA to HETEs and epoxides (EETs) was greater in cortical microsomes than in medullary microsomes. Sodium nitroprusside (10-100 μM), an NO donor, inhibited renal microsomal conversion of [14C]AA to HETEs and EETs in a dose-dependent manner. 8-bromo cGMP (100 μM), the cell-permeable analogue of cGMP, did not affect conversion of [14C]AA. Inhibition of NOS with N(ω)-nitro-L-arginine-methyl ester (L-NAME) significantly increased conversion of [14C]AA to HETE and greatly increased the expression of ω-hydroxylase protein, but this treatment had only a modest effect on epoxygenase activity. L-NAME induced a 4-fold increase in renal efflux of 20-HETE, as did L-nitroarginine. Oral treatment with 2% sodium chloride (NaCl) for 7 days increased renal epoxygehase activity, both in the cortex and the medulla. In contrast, cortical ω-hydroxylase activity was reduced by treatment with 2% NaCl. Coadministration of L-NAME and 2% NaCl decreased conversion of [14C]AA to HETES without affecting epoxygenase activity. Thus, inhibition of NOS increased ω-hydroxylase activity, CYP4A expression, and renal efflux of 20- HETE, whereas 2% NaCl stimulated epoxygenase activity.

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