1 Centro de Investigación y de Estudios Avanzados del Institúto Politécnico Nacional, Mexico DF 07300; 2 Department of Pharmacology, New York Medical College, Valhalla, New York 10595; and 3 College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas 77004
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ABSTRACT |
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We examined the rat
proximal tubule (PT) response to endothelin-1 (ET-1) in terms of
20-hydroxyeicosatetraenoic acid (HETE) dependency. Arachidonic acid
(AA) (1 µM) decreased ouabain-sensitive 86Rb uptake from
2.1 ± 0.1 to 0.3 ± 0.08 ng Rb · 10 µg
protein1 · 2 min
1
(P < 0.05); 20-HETE (1 µM) had similar effects.
Dibromododecenoic acid (DBDD) (2 µM), an inhibitor of
-hydroxylase, abolished the inhibitory action of AA on
86Rb uptake whereas the PT response to 20-HETE was
unaffected. ET-1 at 0.1, 1, 10, and 100 nM reduced 86Rb
uptake from 2.8 ± 0.3 in control PTs to 2.4 ± 0.2, 1.7 ± 0.1, 0.67 ± 0.08, and 0.1 ± 0.03 ng Rb · 10 µg
protein
1 · 2 min
1, respectively.
DBDD (2 µM) abolished the inhibitory effect of ET-1 on
86Rb uptake as did BMS182874 (1 µM), an
ETA-selective receptor antagonist. ET-1 (100 nM)
significantly increased PT 20-HETE release by ~50%, an
effect prevented by DBDD.
N
-nitro-L-arginine-methyl
ester (L-NAME), given for 4 days to inhibit nitric oxide
synthase (NOS), increased arterial pressure from 92 ± 12 to
140 ± 8 mmHg and increased endogenous release of 20-HETE from
isolated PTs (measured by gas chromatography/mass spectrometry). In
L-NAME-treated PTs, but not in control PTs, 0.1 µM AA
inhibited ouabain-sensitive 86Rb uptake by >40%; the
response to AA was attenuated by DBDD. We conclude that, in the PTs,
1) 20-HETE is a second messenger for ET-1 and 2)
conversion of AA to 20-HETE is augmented when NOS is inhibited.
20-hydroxyeicosatetraenoic acid; arachidonic acid metabolites; endothelin-1; nitric oxide
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INTRODUCTION |
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THE RENAL FUNCTIONAL EFFECTS of endothelins have been related to eicosanoid-dependent mechanisms served by cytochrome P-450 (CYP450)-derived arachidonate metabolites (22, 20, 11). A CYP450 arachidonate metabolite, likely 20-hydroxyeicosatetraenoic acid (20-HETE) and its metabolites via cyclooxygenase (COX), the prostaglandin analogs of 20-HETE, contribute substantially to the renal vasoconstrictor and diuretic actions of endothelin-1 (ET-1) (22). The diuretic response to ET-1 is independent of the pressor action of the peptide and is abrogated by inhibition of CYP450 arachidonic acid (AA) metabolism (21), suggesting that ET-1 acts on tubular function via a CYP450-dependent AA metabolite. The similarity of the unique renal functional effects of ET-1 and 20-HETE, namely, diuresis despite renal vasoconstriction and depression of glomerular filtration rate (GFR), is in keeping with the proposal that 20-HETE and its metabolites via COX act as second messengers for the renal vascular and tubular actions of ET-1 (22, 17). Furthermore, ET-1 increases renal efflux of 20-HETE (20).
The proximal tubule (PT) represents an ideal site to study
eicosanoid-dependent mechanisms, particularly those involving CYP450 products that are activated by endothelins: 1) they are
endowed with the highest renal activity of -hydroxylase, the enzyme
responsible for generating 20-HETE (19); 2) COX
activity of the PT is absent or negligible (31), thereby
eliminating or minimizing 20-HETE metabolism by COX, which can
complicate interpretation of 20-HETE-ET-1 interactions; and
3) nitric oxide synthase (NOS) is present in PT (35,
26); this affords the opportunity to study the modulatory influence of NO on 20-HETE-ET-1 interactions, which has been reported to be considerable in the rat kidney (22, 23).
We found that 20-HETE functions as a second messenger, mediating the effects of ET-1 on ion transport in PTs, and inhibition of NOS greatly enhances AA conversion to 20-HETE with attendant augmented effects on PT transport.
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MATERIALS AND METHODS |
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Materials.
ET-1 (Peninsula Laboratories, Belmont, CA) was dissolved in 0.1%
acetic acid; BMS182874
(5-dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalene sulfonamide was dissolved in 0.1 M NaHCO3.
N-nitro-L-arginine-methyl ester
(L-NAME; Sigma), amiloride (Sigma), and ouabain (Sigma)
were dissolved in distilled water. Sigmacote (Sigma) was dissolved in
Hanks' solution and Percoll (Atlanta Biologicals, Norcross, GA)
was dissolved in Tyrode solution. Iron oxide was suspended in Tyrode
solution. Dibromododec-11-enoic acid (DBDD) and 20-HETE (gifts from Dr.
Camille Falck, University of Texas Southwestern Medical Center, Dallas,
TX) were stored in ethanol at
20°C. Sodium arachidonate (Nuchek,
Elysian, MN) was dissolved in distilled water in a stock solution (1 mg/ml) and stored under nitrogen at
70°C. 86Rb
(Amersham International) was supplied in aqueous solution in a stock
concentration of 37 MBq (1 µCi)/ml.
Isolation of PTs. Male Sprague-Dawley rats (180-198 gm) were anesthetized by an intraperitoneal injection of pentobarbital sodium (50 mg/kg). Kidneys were perfused in situ with 10 ml ice-cold Tyrode solution containing 1 mg/ml iron oxide. The renal cortex was separated and minced (1 mm3) with a surgical blade (size 12). The minced cortical tissue was subjected to enzyme digestion at 37°C in oxygenated (95% O2-5% CO2) Tyrode solution containing collagenase (200 U/ml), hyaluronidase (200 U/ml), soybean trypsin inhibitor (0.5 mg/ml), glucose (10 mM), sodium succinate (1 mM), albumin (10 mg/ml), and L-alanine (5 mM). Every 5 min, the supernate of the incubation solution was drawn off and a fresh digestion solution added. A sample of the tissue was removed and examined under a low-power microscope to determine the extent of digestion. After repeating this process 3-4 times, a side-pull magnet (Perspective Biosystems, Framingham, MA) was used to separate the tubule from the iron-containing vascular tissue. Tubular fractions were gently layered onto a 35% Percoll solution and centrifuged for 10 min at 13,000 g. The bottom layer, which contained PTs, was removed for the experiments. The purity of the preparation was 90-95% as confirmed by light microscopy. Protein concentration was determined in PT suspensions using a protein assay kit (Bio-Rad Chemical Division, Richmond, CA).
86Rb uptake.
86Rb uptake was determined using the method we described
previously (6). Briefly, freshly isolated PTs were
preincubated on ice for 20 min in K+-free (substitution of
NaCl for KCl on a mole-for-mole basis) Hanks' buffered saline solution
(HBSS), pH 7.4, with 5.5 mM glucose as the sole substrate. In
preliminary experiments (n = 6), optimal incubation
time was established for 86Rb uptake by determining uptake
in PTs (100 µg protein) incubated in KCl solution (final
K+ concentration, 5 mM) containing 86Rb (0.7 µCi) in a shaking water bath (37°C) for different times: 0, 0.5, 1, 2, 5, 10, and 15 min. Isotope uptake was terminated by the addition of
100 µl of a stop solution (Sigmacote) to cell suspension, which was
pelleted (13,000 g × 30 s) immediately. Specific
activity of 86Rb in the pellet was determined using a
scintillation counter (Beckman LS 1301). 86Rb uptake by PTs
was calculated from standards and expressed as ng Rb · 10 µg
protein1 · 2 min
1. Because of
interexperimental variations, 86Rb uptake was performed in
the presence of ouabain (1 mM) in each experiment to evaluate
ouabain-sensitive 86Rb uptake, which was calculated by
subtracting 86Rb uptake in the presence of 1 mM ouabain
from that in its absence. Comparability of data was assessed by
evaluating the degree of ouabain inhibition of 86Rb uptake
(positive control). The ion transport mechanisms were evaluated by
determining 86Rb uptake in PTs pretreated for 10 min with
ouabain (1 mM; n = 5), the
Na+-K+-ATPase inhibitor, or amiloride (1 mM;
n = 5), an inhibitor of the
Na+/H+ exchanger (Fig.
1).
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PT production of 20-HETE.
The amount of 20-HETE produced in isolated PTs was determined by gas
chromatography/mass spectrometry (GC/MS) using the methods previously
described (20). Fifty micrograms of PT tissue protein from
control- or L-NAME-treated rats was incubated in PBS, pH 7.4, containing CaCl2 (1.2 mM), glucose (11 mM), NADPH (1 mM), and phenanthroline (1.2 mM) in the presence or absence of ET-1 (1, 10, and 100 nM) for 10 min at 37°C. The reaction was terminated by
the addition of 500 µl ethanol containing 0.5 ng of
[20,202 H2]20-HETE as an internal standard.
After total lipid extraction with ethyl acetate, the final dried
extract was subjected to GC/MS analysis to determine the amount of
20-HETE released into the medium. Data were expressed as nanograms of
20-HETE released per micrograms of PT protein.
Data analysis. All data are expressed as means ± SE. Statistical significance was determined by ANOVA, followed by a modified Student's t-test for specific comparison. In all cases, P < 0.05 was considered significant.
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RESULTS |
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Ion transport in freshly isolated PTs.
In preliminary experiments, we established that 86Rb uptake
increased in a time-dependent manner and reached saturation after 10 min. Ouabain (1 mM) and amiloride (1 mM) inhibited 86Rb
uptake by 68 ± 7 and 74 ± 4%; viz, from 5.1 ± 0.84 to 2.04 ± 0.48 and 1.67 ± 0.22 ng Rb · 10 µg
protein1 · 2 min
1, respectively,
indicating that an active Na+-K+-ATPase and
Na+/H+ exchanger regulate ion transport in rat
PTs (Fig. 1). The magnitude of inhibition by ouabain was similar
(range, 63-68%) in all experiments, suggesting that differences
in experimental conditions, in the absence of direct interventions, did
not affect ion transport in PTs.
Effects of AA and 20-HETE on ion transport in PTs.
To examine the participation of a transport mechanism related to
CYP450-AA metabolism in PT, the effect of AA (1 µM) on
86Rb uptake by PTs was determined in the absence or
presence of DBDD (2 µM), an inhibitor of CYP450-dependent AA
metabolism (35). AA decreased 86Rb uptake from
2.1 ± 0.1 to 0.3 ± 0.08 ng Rb · 10 µg
protein1 · 2 min
1
(n = 5) as did 20-HETE (1 µM; n = 5)
(Fig. 2). Coincubation with DBDD (2 µM)
abolished the inhibitory effect of AA on 86Rb uptake by
PTs, suggesting that a CYP450-AA product inhibited 86Rb
uptake. DBDD did not affect the response to 20-HETE.
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Effects of ET-1 on ion transport, prevention by ETA
receptor antagonism, and the role of 20-HETE.
ET-1 decreased 86Rb uptake in freshly isolated PTs in a
dose-dependent manner (Fig. 3). ET-1 at
0.1, 1, 10, and 100 nM reduced 86Rb uptake from 2.8 ± 0.3 in control PTs to 2.4 ± 0.2, 1.7 ± 0.1, 0.67 ± 0.08, and 0.1 ± 0.03 ng 86Rb · 10 µg
protein1 · 2 min
1, respectively.
BMS182874 (1 µM), an ETA-selective receptor
antagonist (33), abolished the decrease in PT
86Rb uptake produced by ET-1 (10 nM) (Fig.
4). DBDD (2 µM), which was without
effect on basal 86Rb uptake, abolished the inhibitory
effect of 10 nM ET-1 on 86Rb uptake, suggesting that the
effects of ET-1 were mediated by a CYP450-AA metabolite (Fig.
5). PT production of 20-HETE was evaluated in preparations to which ET-1 was added (Fig.
6). Basal production of 20-HETE was
0.83 ± 0.22 ng/µg protein and was decreased by DBDD (2 µM) to
0.45 ± 0.05 ng/µg protein (P < 0.05).
Incubation of PTs with ET-1 significantly increased 20-HETE release
only in response to 100 nM ET-1; viz, to 1.21 ± 0.22 ng/µg
protein (P < 0.05), an effect that was prevented by
DBDD.
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Effects of L-NAME treatment on AA-induced inhibition of
86Rb uptake by PTs.
L-NAME treatment for 4 days increased carotid arterial
blood pressure from 92 ± 12 to 140 ± 8 mmHg
(P < 0.05) and decreased plasma nitrite concentration
from 275 ± 66 to 150 ± 50 µM (P < 0.05)
for control (n = 5) and L-NAME-treated
(n = 5) rats, respectively. Concomitant with these
changes, L-NAME treatment increased endogenous production
of 20-HETE in isolated PTs to 2.4 ± 0.5 from 1.4 ± 0.2 ng/µg protein in control rats (P < 0.05) (Fig.
7). DBDD (2 µM) inhibited 20-HETE
production in PTs obtained from both control and
L-NAME-treated rats. L-NAME potentiated the
inhibitory effect of AA on ouabain-sensitive 86Rb uptake;
viz, in PTs from L-NAME-treated rats, AA (0.1 µM)
inhibited 86Rb uptake by ~40% in contrast to no effect
at the same concentration of AA in vehicle-treated rats, and AA (1 µM) inhibited ouabain-sensitive AA uptake by 55% before
L-NAME treatment and 78% after (P < 0.05) (Fig. 8). DBDD (2 µM) attenuated the
inhibitory effect of 0.1 and 1.0 µM AA on 86Rb uptake in
L-NAME-treated rats, suggesting that a CYP450-AA metabolite, likely 20-HETE, mediated the responses to AA.
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DISCUSSION |
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The CYP450 monooxygenases, which can be activated by ET-1
(22), generate AA metabolites acting on the renal
vasculature and tubules to regulate volume and composition of body
fluids (10, 17). As the renal effects of ET-1 resemble
those of 20-HETE and are unique (21), viz, natriuresis in
the face of negative hemodynamic effects, we hypothesized that a
significant component of the natriuretic-diuretic action of ET-1 was
mediated by 20-HETE as a result of inhibition of ion transport by the
eicosanoid in the PTs. We also postulated that inhibition of NOS would
potentiate 20-HETE-mediated effects on PT ion transport in view of the
tonic inhibitory action exerted by NO on -hydroxylase activity, the enzyme that synthesizes 20-HETE (1, 26). Our results
indicate that: 1) ET-1 affected ion transport in rat PTs via
a CYP450-dependent eicosanoid mechanism involving 20-HETE as DBDD, an
inhibitor of
-hydroxylase (34), attenuated ET-1 induced
reduction of 86Rb uptake, and 20-HETE mimicked ET-1
inhibition of 86Rb uptake; 2) elimination of the
inhibitory effect of NO on
-hydroxylase increased AA conversion by
-hydroxylase to 20-HETE (1, 22) and, thereby,
potentiated CYP450-dependent AA effects on PT ion transport (Fig. 8);
and 3) ET-1 has the capacity to release 20-HETE from PTs
(Fig. 6). It should be noted that the potency of ET-1 for releasing
20-HETE is greatly underestimated because of the rapid disposition of
newly synthesized 20-HETE by metabolism, conjugation, and incorporation
into phospholipids (17).
CYP450-derived eicosanoids, the HETEs and epoxyeicosatrienoic acids, affect ion transport and water movement and are released in response to hormones that affect tubular function (17); they act as second messengers/mediators as well as modulators of salt and water excretion at several sites in the nephron: cortical collecting tubules (12), PTs (28, 32), and medullary thick ascending limb of the loop of Henle (mTAL) (5). Moreover, CYP450 arachidonate metabolites may affect tubular function through several mechanisms: 1) inhibition of Na+-K+-ATPase (30, 3); 2) activation of the Na+/H+ exchanger (9); 3) inhibition of arginine vasopressin-stimulated water reabsorption in the collecting duct (10); and 4) facilitation of calcium entry associated with inhibition of Na+ transport in PTs in response to high-dose angiotensin II (28).
The principal renal CYP450 eicosanoid, 20-HETE, is generated by key
nephron segments, the mTAL (3) and PTs (19),
the latter having the highest activity of -hydroxylase in the
nephron (19). PT CYP450 AA metabolism can be stimulated by
peptide hormones and shows selectivity in response to hormonal
challenge: parathyroid hormone and epidermal growth factor stimulate
20-HETE production whereas angiotensin II has a selective effect on
epoxyeicosatrienoic acid production (19). The importance
of 20-HETE production to the renal actions of ET-1 was demonstrated
in two recent studies: 1) the renal vasoconstrictor and
diuretic-natriuretic response to ET-1 in the euvolemic
anesthetized rat was blunted by inhibiting 20-HETE production
(21); and 2) the precipitous decline in GFR, pressor response, and diuresis-natriuresis, evoked by inhibiting NO
production with L-NAME, was attenuated by either blockade
of endothelin receptors or inhibiting synthesis of 20-HETE
(22).
Involvement of endothelins in the regulation of PT transport is supported by several studies: 1) endothelins are synthesized by PTs (14); 2) endothelin binding sites have been identified in PTs (15); 3) ET-1 affects bulk flow in isolated perfused straight segments of PTs (7); and 4) ET-1 inhibits PT Na+-K+-ATPase, a principal determinant of transcellular Na+ movement in the nephron (8). Furthermore, ET-1 effects on tubular ion transport have been related to eicosanoid-dependent mechanisms, which is not unexpected, in view of the ability of endothelins to stimulate phospholipases, releasing AA for conversion to eicosanoids (2, 8). For example, ET-1 activates prostaglandin-dependent mechanisms in the collecting duct to promote diuresis-natriuresis (36). More to the point, ET-1 has been suggested to stimulate AA metabolism via both lipoxygenases and cyclooxygenases in PTs (7), producing eicosanoids that contribute to the diuresis-natriuresis evoked by the peptide. A key target for eicosanoids in both collecting ducts and PTs is Na+-K+-ATPase, the sodium pump, an essential component in tubular mechanisms governing renal sodium reabsorption. The sodium pump of PTs appears to be the critical point of convergence of mechanisms involving ET-1 and 20-HETE in regulating sodium reabsorption, as each inhibits PT Na+-K+-ATPase, ET-1 indirectly via stimulating 20-HETE synthesis, which in turn activates protein kinase C (PKC) (18) that inhibits the sodium pump. Inhibition of PT sodium reabsorption by this mechanism, involving a CYP450 AA product, likely 20-HETE, and PKC also appears to be utilized by dopamine (29) and parathyroid hormone (24), as well as by ET-1.
NO regulates the activities of both the endothelin and CYP450 systems (21). NO prevents, whereas inhibition of NO synthesis promotes, the expression and production of ET-1 in cultured endothelial cells (16). NO also inhibits hemoproteins, including CYP450 enzymes (13).
Inhibition of NOS in the anesthetized rat uncovers a major
vasoconstrictor diuretic-natriuretic system operating through one or
more CYP450-dependent metabolites generated by -hydroxylases (22). We tested the hypothesis that inhibition of NOS
affects CYP450-AA metabolism in PTs by comparing the effects of AA on ion transport in rats before and after treatment with an NOS inhibitor. L-NAME-treated rats demonstrated potentiation of
CYP450-dependent AA-induced reduction in 86Rb uptake (Fig.
8) associated with increased 20-HETE release by PTs (Fig. 7),
indicating that a CYP450-dependent ion transport mechanism involving
-hydroxylase was disinhibited when NO production was blocked. Thus
after L-NAME treatment, a concentration of AA (0.1 µM),
which had been without effect on 86Rb uptake, showed a
greater than 40% inhibition of ouabain-sensitive 86Rb
uptake (Fig. 8), an effect of AA attenuated by inhibition of
-hydroxylase, indicating that conversion of AA to 20-HETE was involved. These findings are in accord with our in vivo studies regarding the effects of both L-NAME and ET-1 on sodium
excretion; namely, that natriuresis was blocked by inhibition of
20-HETE synthesis and was independent of their pressor effects. These findings also complement those of earlier studies (27, 35) that recognized the potential importance of NO in modulating PT sodium reabsorption.
The present study, as well as our recent in vivo studies, provide a mechanism for the diuretic-natriuretic response to inhibition of NOS; namely, 20-HETE mediates a significant component of the tubular effects produced by suppression of NO formation as the synthesis of 20-HETE, which is subject to tonic inhibition by NO, is greatly enhanced when NO production is blocked. There are several issues that have not been resolved by the present study. The claims of previous studies for both lipoxyygenase and COX representation in PTs and their activation by ET-1 was based on 1) renal clearance methods in a study that identified a lipoxygenase interacting with endothelins (25), and 2) perfusion of the isolated straight segment in a study that indicated involvement of both COX and lipoxygenase interacting with ET-1 to affect sodium transport (7). A direct comparison of our study with the aforementioned studies is difficult, if not precluded, given marked differences in the experimental preparations and design as well as in methods. We have attempted to allay concerns regarding claims made for the involvement of 20-HETE in the PT effects of ET-1 by measuring the release of 20-HETE from PTs. Moreover, we obtained evidence for the ability of DBDD to inhibit synthesis of 20-HETE. One area, namely, the positive effects of very low concentrations of ET-1 (pM) on PT sodium transport (7), was not addressed, as our intention was to focus on the natriuretic component of the PT action of ET-1, because this area of the dose-response curve to ET-1 was postulated to involve a 20-HETE dependency, which the present study supports.
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ACKNOWLEDGEMENTS |
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The authors thank Dr. J. R. Falck for supplying 20-HETE and DBDD, Dr. John Quilley for assistance with the manuscript, and Barbara Stern and Melody Steinberg for preparation of the manuscript and editorial assistance.
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FOOTNOTES |
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This research was supported by National Heart, Lung, and Blood Institute Grants RO1-HL-25394 and PPG-HL-34300 (to J. C. McGiff); RO1-HL-59884, UH1-HL-03674, and an Established Investigator Award of the American Heart Association 0040119N (to A. O. Oyekan); and Grant RO3-TW00706 (Fogarty International Collaborative Award) and the Mexican Council of Science and Technology, Mexico (to B. A. Escalante).
Address for reprint requests and other correspondence: J. C. McGiff, Dept. of Pharmacology, New York Medical College, Valhalla, NY 10595 (E-mail: John_McGiff{at}nymc.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published August 21, 2001; 10.1152/ajprenal.00064.2001
Received 26 February 2001; accepted in final form 20 August 2001.
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