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cotransport via a cytochrome P-450-dependent
pathway in renal epithelial cells (MMDD1)
Department of Medicine, Ottawa Hospital, and the Kidney Research Centre, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada K1H 8L6
Nitric oxide (NO) exerts direct
effects on nephron transport. We determined the effect of NO on
Na+-K+-2Cl
cotransport in a cell
line (MMDD1) with properties of macula densa.
Na+-K+-2Cl cotransport was
measured as bumetanide-sensitive 86Rb+ uptake
in the presence of ouabain. MMDD1 cells expressed mRNA for the neuronal
isoform of nitric oxide synthase, as well as NKCC1 and NKCC2(B)
isoforms of the Na+-K+-2Cl
cotransporter. Preincubation of cells with the NO donors sodium nitroprusside (SNP) or
S-nitroso-N-acetylpenicillamine (SNAP) caused
concentration-dependent inhibition of
Na+-K+-2Cl cotransport. Both
apical and basolateral Na+-K+-2Cl
cotransport was inhibited by NO donors. SNP or SNAP had no significant effect on cellular levels of cGMP, cAMP, cytosolic calcium, or phosphorylation of ERK1 and ERK2. In contrast, the inhibitors of
cytochrome P-450, 1-aminobenzotriazole (ABT;
103 M) or ketoconazole (1.5 × 105 M),
completely reversed the inhibitory effect of SNAP on apical or
basolateral Na+-K+-2Cl
cotransport [apical: control 1.18 ± 0.15 vs. SNAP
(104 M) 0.41 ± 0.05 pmol · mg1 · 5 min1; P < 0.001; SNAP (104
M) + ABT 1.32 ± 0.10 pmol · mg1 · 5 min1; P = not significant vs. control;
n = 5]. The cytochrome P-450 epoxyeicosatrienoic acid (EET) metabolite 14,15-EET (5 × 107 M) inhibited both apical and basolateral cotransport,
whereas 8,9-EET and 11,12-EET had no significant effect. Although
20-hydroxyeicosatetraenoic acid inhibited apical cotransport, the
inhibitor of 
-hydroxylase activity HET0016 did not reverse
SNAP-mediated inhibition of apical cotransport. These data indicate
that NO inhibits apical and basolateral Na+-K+-2Cl cotransport in MMDD1
cells. The results suggest that the inhibitory pathway is independent
of cGMP and might involve stimulation of a cytochrome
P-450-dependent pathway.
NKCC1; NKCC2; nitric oxide synthase; epoxyeicosatrienoic acids
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