TY - JOUR
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.
PY - 1999/10
Y1 - 1999/10
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.
UR - http://www.scopus.com/inward/record.url?scp=0032747358&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032747358&partnerID=8YFLogxK
U2 - 10.1172/JCI6786
DO - 10.1172/JCI6786
M3 - Article
C2 - 10525052
AN - SCOPUS:0032747358
SN - 0021-9738
VL - 104
SP - 1131
EP - 1137
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 8
ER -