1 Department of Woman and Child Health, Pediatric Unit, Karolinska Institute, S-171 76 Stockholm, Sweden; and 2 Centro de Investigaciones Endocrinologicas, Consejo Nacional de Investigaciones Cíentificas y Técnicas, 1425 Buenos Aires, Argentina
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ABSTRACT |
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Locally formed arachidonic acid (AA)
metabolites are important as modulators of many aspects of renal
tubular function, including regulation of the activity of tubular
Na+-K+-ATPase. Here we examined the ontogeny of
the AA metabolic pathways regulating proximal convoluted tubular (PCT)
Na+-K+-ATPase activity in infant and adult
rats. Eicosatetraynoic acid, an inhibitor of all AA-metabolizing
pathways, abolished this effect. AA inhibition of PCT
Na+-K+-ATPase was blocked by the
12-lipoxygenase inhibitor baicalein in infant but not in adult rats and
by the specific cytochrome P-450 fatty acid -hydroxylase
inhibitor 17-octadecynoic acid in adult but not in infant rats. The
lipoxygenase metabolite 12(S)-hydroxyeicosatetraenoic acid (HETE) and
the cytochrome P-450 metabolite 20-HETE both inhibited PCT
Na+-K+-ATPase in a protein kinase C-dependent
manner, but the effect was significantly more pronounced in infant PCT.
Lipoxygenase mRNA was only detected in infant cortex. Expression of
renal isoforms of cytochrome P-450 mRNA was more prominent in
adult cortex. In summary, the AA metabolic pathways that modulated the
activity of rat renal proximal tubular
Na+-K+-ATPase are age dependent.
renal cytochrome P-450; 12-lipoxygenase; protein kinase C; 12-hydroxyeicosatetraenoic acid; 20-hydroxyeicosatetraenoic acid
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INTRODUCTION |
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SEVERAL LINES OF EVIDENCE suggest that arachidonic acid (AA) metabolites play important roles in the regulation of renal function (5, 15, 27). For example, the activity of Na+-K+-ATPase in proximal tubules, collecting duct, and medullary thick ascending limb of the loop of Henle is modulated by AA metabolites (8, 18, 23, 25, 26). These effects are of great physiological importance because the enzyme Na+-K+-ATPase generates energy for the tubular absorption of Na+.
AA is released from membrane lipids in response to receptor-dependent as well as receptor-independent activation of phospholipase A2 (PLA2) (3, 6, 25). Free AA can be metabolized to biologically active metabolites by three enzyme systems, namely, the cyclooxygenase pathway, the lipoxygenase pathway, and the cytochrome P-450 monooxygenases pathway. There are indications from experimental studies that in rat kidney the cytochrome P-450 monooxygenases pathway is influenced by the state of maturation (21, 27) and may be also upregulated in pathological conditions, such as spontaneous hypertension (21, 22, 27) and salt-sensitive hypertension (14).
There are profound alterations in the regulation of Na+ excretion during ontogeny (1, 9, 20). This has prompted us to examine the ontogeny of the AA-metabolizing pathways involved in the regulation of renal tubular Na+-K+-ATPase activity. We report here that the AA-lipoxygenase pathway, that has hitherto been considered to be of little importance for the regulation of renal proximal tubular function, plays a physiological role in modulation of renal tubular Na+-K+-ATPase in infant rats. This pathway is downregulated during ontogeny. In accordance with previous studies, we found that adult rats use the cytochrome P-450 pathway to regulate proximal convoluted tubule (PCT) Na+-K+-ATPase (18, 23, 25, and this study).
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MATERIALS AND METHODS |
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Animals. Male Sprague-Dawley rats (B&K Universal, Sollentuna, Sweden) aged 9-11 (infant) and 39-45 days (adult) were used. Body weights were 22-32 and 150-200 g, respectively. The pups were kept with their dams, and the adult rats were fed a standard rat chow (B&K Universal) ad libitum and had free access to tap water.
Chemicals. AA was purchased from Nu Chek Prep (Elysian, MN); 20- hydroxyeicosatetraenoic acid (HETE), 12(S)-HETE, and 12(R)-HETE from Cascade Biochem (Berkshire, UK); 17-octadecynoic acid (17-ODYA) from Cayman Chemical (Ann Arbor, MI); and baicalein and bisindolylmaleimide (GF-109203X) from Calbiochem (La Jolla, CA). Eicosatetraynoic acid (ETYA), nordihydroguaiaretic acid (NDGA), and all other chemicals were purchased from Sigma Chemical (St. Louis, MO). AA, 20-HETE, and 12(S)-HETE and inhibitors of AA metabolism were dissolved in ethanol. GF-109203X was dissolved in DMSO. Final concentrations of ethanol and DMSO in incubation media were shown not to interfere with Na+-K+-ATPase activity in control experiments.
Microdissection of single tubular segment and determination of
Na+-K+-ATPase
activity.
Na+-K+-ATPase activity in PCT segments was
measured as previously described (16). PCT segments (length 0.5-1
mm) were dissected from collagenase (0.05%)-perfused rat kidney. The
tubular segments were preincubated with or without the addition of
drugs for 30 min at room temperature in 1 µl of oxygenated modified
Hanks' solution (MHS) containing (in mM) 137 NaCl, 5 KCl, 0.8 MgSO4, 0.33 Na2HPO4, 0.44 KH2PO4, 0.25 CaCl2, 1 MgCl2, and 10 Tris · HCl. Butyrate
(103 M) was added to the solution to
optimize mitochondrial respiration. After preincubation in MHS with or
without drugs, MHS was removed and ice-cold ATPase assay solution, with
compositions described below, was added. The segments were
permeabilized with rapid freezing and thawing in the ATPase assay
solution to ensure that Na+ and ATP entered the cell. The
Na+ concentration in the medium was 70 mM. Permeabilization
clamps the intracellular Na+ concentration and the
Na+ concentration in the medium, thereby eliminating the
transmembrane Na+ gradient and the possibility that changes
in Na+-K+-ATPase activity are secondary to
changes in intracellular Na+ concentration. All
Na+-K+-ATPase assays were performed in the
presence of saturating concentrations of all major substrates (70 mM
Na+, 5 mM K+, and 10 mM ATP). After
preincubation and permeabilization, the tubule segments were incubated
for 15 min at 37°C in the ATPase assay solution (in mM): 50 NaCl, 5 KCl, 10 MgCl2, 1 EGTA, 100 Tris · HCl,
and 10 Na2ATP, as well as 2-5 Ci/mmol
[
-32P]ATP in tracer amounts (5 nCi/µl), pH
7.4, at 37°C with or without 2 mM ouabain. When ouabain was
present, NaCl and KCl were omitted and Tris · HCl was
150 mM. The phosphate liberated by hydrolysis of
[
-32P]ATP was separated by filtration
through a Millipore filter after absorption of the unhydrolyzed ATP on
activated charcoal. The radioactivity was measured in a liquid
scintillation spectrophotometer. In each study (each rat), total ATPase
activity was measured in five to eight segments, and
ouabain-insensitive ATPase activity was measured in five to eight
segments. Na+-K+-ATPase activity was calculated
as the difference between the means of the total ATPase and the
ouabain-insensitive ATPase activity and was expressed as picomoles
32P hydrolyzed per millimeter tubule per hour. Results are
given as the percentage of control.
Purification of rat renal
Na+-K+-ATPase.
Na+-K+-ATPase was purified from adult rat renal
cortex as described (11). The preparation was analyzed by SDS-PAGE. The
gel was stained with Coomassie brilliant blue. Densitometric analysis of the stained gel indicated that the
Na+-K+-ATPase -subunit constituted ~55%
of total proteins in the preparation. The specific activity of
Na+-K+-ATPase in the preparation was calculated
as ~700 µmol of ATP hydrolyzed · mg
protein
1 · h
1.
The ouabain (5 mM)-insensitive ATPase activity was <3% of total ATPase activity.
Phosphorylation of purified
Na+-K+-ATPase
by protein kinase C (PKC).
Assays were carried out at 24°C in a reaction volume of 20 µl
containing (in mM) 50 HEPES (pH 7.5), 0.85 CaCl2, 10 MgCl2, and 1 EGTA, as well as 10 nM PKC and 1 µg of
purified Na+-K+-ATPase. Reactions were
initiated by the addition of ATP (final concentration 0.1 mM), with a
trace of [-32P]ATP (2,000-3,000
cpm/pmol). Reactions were stopped by the addition of Laemmli sample
buffer. Samples were resolved by 7.5% SDS-PAGE. Gels were stained with
Coomassie brilliant blue, destained, dried, and analyzed by
autoradiography or the Bio-Rad Molecular Imager Phosphor Imaging System
(model GS-250).
Gene expression analysis by semiquantitative RT-PCR. Renal cortical slices (200 µm thick) from the superficial cortex were used. These slices consist mainly (>90%) of proximal tubules (2). Because leukocytes and thrombocytes express lipoxygenase (34), blood was removed from the renal vasculature by perfusing the left kidney with cold Ringer solution until blanched. Quantitative microscopy inspection of digested slices showed that fewer than two glomeruli per slice were present in slices from either adult or infant rats (data not shown).
The method for RT-PCR was modified from the one previously described (36). Reverse transcription was carried out in a 10-µl reaction volume containing 1 µg total RNA, 25 mM Tris · HCl (pH 8.3), 37.5 mM KCl, 1 mM deoxynucleotide triphosphates (dNTPs), 5.0 mM dithiothreitol (DTT), 0.4 µM oligo(dT15) primer, 20 U RNasin, 80 U Moloney murine leukemia virus RT, and RNase H Minus (Promega) and incubated for 60 min at 42°C, followed by 10 min at 95°C. The RT reaction was converted to a 100-µl PCR containing 2.5 U thermostable DNA polymerase (AmpliTaq Gold, Stratagene), 0.2 µM of each gene-specific primer (see Table 1), 200 µM dNTPs, 300 nCi [32P]dCTP, 10 mM Tris · HCl (pH 8.8), 1.5 mM MgCl2, 50 mM KCl, and 0.1% Triton X-100 and sequentially cycled for 20-35 cycles. The reaction mixture was incubated in a Perkin-Elmer Cetus 9600 thermocycler (55°C for 45 s, 72°C for 90 s, 95°C for 30 s), starting at 95°C for 10 min and finishing at 72°C for 5 min. All gene-specific primer pairs used in the RT-PCR protocols are shown in Table 1.
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Statistical analysis. Values represent means ± SE. Data were analyzed by the Student's t-test or ANOVA-test. P values < 0.05 are considered significant.
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RESULTS |
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Under basal condition, Na+-K+-ATPase activity
(in pmol
Pi · mm1 · h
1)
was 909 ± 34 (n = 20) in infant rat PCT and 1,663 ± 147 (n = 27) in adult rat PCT. AA produced a dose-dependent
inhibition of the activity of Na+-K+-ATPase in
PCT from both infant and adult rats. The maximal inhibition was ~45%
(Fig. 1A). The concentrations
required to evoke PCT Na+-K+-ATPase inhibition
were somewhat lower in infant rats. The inhibitory effect of AA was
completely abolished by a specific PKC inhibitor, GF-109203X (1 µM),
in both infant and adult rats (Fig. 1B). Basal Na+-K+-ATPase activity was not altered by
GF-109203X alone (adult rats: control 2,023 ± 190, GF-109203X 2,130 ± 268; infant rats: control 974 ± 45, GF-109203X 920 ± 80 pmol
Pi · mm
1 · h
1).
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To assess whether the inhibitory effect of AA was mediated by its
metabolites, inhibitors of different AA metabolic pathways were used.
ETYA is an inhibitor of all AA enzymatic metabolizing pathways (26,
32). Figure 2 shows that ETYA completely
blocked AA-induced Na+-K+-ATPase inhibition in
PCT from both infant and adult rats. This observation rules out a
direct effect of AA and strongly suggests the involvement of AA
metabolites in the inhibition of renal tubular Na+-K+-ATPase. The major AA metabolic pathway
operating in the proximal tubules from adult rats involves the
cytochrome P-450 AA -hydroxylase pathway, resulting in the
generation of 20-HETE (22, 27). Alternatively, AA may be also
oxygenated by 12-lipoxygenase present, for instance, in platelets and
vascular smooth muscle cells (17), leading to the formation of
12(S)-HETE. A specific inhibitor of the cytochrome P-450
pathway, 17-ODYA (1 µM) (37), completely prevented the effect of AA
in adult but had no effect in infant rats. Two inhibitors of the
lipoxygenase pathway were used, namely, 5 µM NDGA and 5 µM
baicalein (30, 31). At the present time baicalein is considered to be
the most specific inhibitor of 12-lipoxygenase. Both NDGA and baicalein
blunted AA-induced Na+-K+-ATPase inhibition in
infant but had no effect in adult rats (Fig. 2). The inhibitors, added
singly, had no effect on Na+-K+-ATPase activity
(adult rats: control 2,159 ± 185, 5 µM ETYA 1,945 ± 333, 1 µM
17-ODYA 2,038 ± 234, 5 µM NDGA 2,475 ± 79, 5 µM baicalein 2,084 ± 260; infant rats: control 868 ± 103, 10 nM ETYA 883 ± 85, 1 µM 17-ODYA 1,054 ± 208, 5 µM NDGA 928 ± 161, 5 µM baicalein 761 ± 42 pmol
Pi · mm
1 · h
1).
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We next tested the effect of metabolites from the lipoxygenase and the
cytochrome P-450 pathways, 12(S)-HETE and 20-HETE (Fig. 3). In this protocol, control values in
infant rats were 1,046 ± 99 (n = 6) and 858 ± 117 (n = 6) for 12(S)-HETE and 20-HETE groups, respectively; in
adult rats they were 2,577 ± 35 (n = 6) and 2,850 ± 112 pmol
Pi · mm1 · h
1
(n = 10) for 12(S)-HETE and 20-HETE groups, respectively. The lipoxygenase metabolite 12(S)-HETE inhibited
Na+-K+-ATPase in both infant and adult PCT, but
inhibition was significantly (P < 0.01) more pronounced in
the infant rats. In contrast, the cytochrome P-450 metabolite
20-HETE inhibited Na+-K+-ATPase activity to a
similar extent in infant and adult PCT. Inhibition by 12(S)-HETE and
20-HETE was abolished by the specific PKC inhibitor GF-109203X in both
infant and adult PCT (data not shown). 12(R)-HETE, another cytochrome
P-450 metabolite that has been shown to inhibit PCT
Na+-K+-ATPase in adult rats (23), was also
found to inhibit the Na+-K+-ATPase in infant
rats (data not shown).
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20-HETE has been recently shown to contribute to the activation of PKC
(18). 12(S)-HETE was shown here to have a similar effect. In vitro
PKC-dependent phosphorylation of the purified rat renal
Na+-K+-ATPase -subunit was increased in the
presence of 12(S)-HETE at the physiological Ca2+
concentration of 1.3 µM (Fig. 4).
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The mRNA expression of 5-lipoxygenase, 12-lipoxygenase, and the
cytochrome P-450 4A1 and 4A2 isoforms was semiquantitatively evaluated by use of RT-PCR. No signal from 5-lipoxygenase mRNA was
detected in slices from outer cortex of infant and adult kidneys (Fig.
5), which confirmed that the slices were
indeed deprived of blood and glomeruli-free (see Gene expression
analysis by semiquantitative RT-PCR). 12-Lipoxygenase
mRNA signal was only detected in cortical tissue from infant rats (Fig.
5). The samples were run at 25, 30, and 35 cycles. Shown in Fig. 5 are
samples run at 35 cycles. 12-Lipoxygenase mRNA was not detected even at
35 cycles in samples from adult rats. Cytochrome P-450 4A1 mRNA
signal was detected in both infant and adult rats at approximately
equal levels (Fig. 6A). However,
there were pronounced qualitative and quantitative differences between
infant and adult rats with regard to the mRNA signal of cytochrome
P-450 4A2 isoform. Two alternative spliced forms of the
cytochrome P-450 4A2 isoform were observed and confirmed with
sequencing in cortex from adult rat. The longer form had 389 bp, and
the shorter form had 267 bp. The splicing occurs in exon 12. The longer
transcript was expressed in both age groups, but it was 3.6-fold more
abundant in adult than in infant rats (Fig. 6, B and
C). The shorter transcript was strongly expressed in adult rats
but was not detectable in infant rats (Fig. 6, B and
C). The total level of the two transcripts for cytochrome P-450 4A2 was ~33-fold higher in adult than in infant rats
(Fig. 6C).
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DISCUSSION |
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The PLA2-AA signaling pathway has recently received a great
deal of attention because of its role in the regulation of
Na+-K+-ATPase activity (18, 23, 25, 26) and of
other tubular transporters. The first messengers activating renal
PLA2 include dopamine, vasopressin, bradykinin, parathyroid
hormone, and angiotensin (23, 25, 26). Only the cytochrome
P-450 metabolites are responsible for the regulation of
Na+-K+-ATPase in PCT from adult rats (23, 25).
The cytochrome P-450-AA--hydroxylase pathway is the
predominant AA metabolic pathway for the regulation of PCT
Na+-K+-ATPase in adult rats (13, 22, 27). The
present results indicate that, in infant rat renal PCT, the
lipoxygenase pathway plays the predominant role for the regulation of
Na+-K+-ATPase activity and that this pathway is
downregulated during postnatal maturation of the kidney. Thus
12-lipoxygenase mRNA was expressed in PCT cells from infant rats but
not detectable in adult rats. The AA-lipoxygenase pathway was involved
in the inhibition of PCT Na+-K+-ATPase in
infant rats but not in adult rats. To our knowledge, this is the first
demonstration of a physiologically active AA lipoxygenase metabolite in
renal PCT. It is well established that lipoxygenase metabolites
regulate cellular responses in inflammation and immunity (24). In
addition, they may also have growth-promoting effects. 12(S)-HETE
mediates cytokine- and phenylephrine-induced mitogenesis in vascular
smooth muscle cells (17). It is therefore possible that in the infant
kidney 12(S)-HETE may also be an important factor in the regulation of
the growth and maturation of nephrons.
Schwartzman and co-workers (29) were the first to demonstrate that
cytochrome P-450 metabolites of AA could inhibit the activity
of Na+-K+-ATPase. The same group has also
reported that the formation of 20-HETE remains at comparable levels
from the fetal stage to 3 wk of age in Wistar-Kyoto kidney cortex. From
3 to 5 wk of age there is an abrupt increase in cytochrome
P-450-AA--hydroxylase activity (responsible for generation
of 20-HETE), which lasts until 13 wk of age (21). These functional
changes can well be explained by increased mRNA expression of
cytochrome P-450 isoforms. The cytochrome P-450 4A gene
family, responsible for AA
-hydroxylation, comprises several
isoforms with great homology (28). Here we have studied the cytochrome
P-450 4A1, which has been considered to be the predominant
isoform catalyzing the formation of 20-HETE from AA in the rat PCT (13)
and the cytochrome P-450 4A2 isoform because it is hormonally
regulated (10) and therefore may be developmentally regulated. We
observed that although there was no detectable difference between the
expression of the cytochrome P-450 4A1 mRNA in infant and adult
kidney, there were pronounced qualitative and quantitative differences
between infant and adult rats with regard to the mRNA signal of the
cytochrome P-450 4A2 isoform. The data on the effects of the AA
metabolites on Na+-K+-ATPase activity suggested
that the cytochrome P-450 pathway participates in the
inhibition of PCT Na+-K+-ATPase in adult rats
but is of minor physiological importance in infant rats. Taken
together, our results indicate that the AA-lipoxygenase pathway is
downregulated and the AA-cytochrome P-450 pathway may be
upregulated with age.
It has been shown that cytochrome P-450 4A1 mRNA exhibits alternative splicing (7). We observed splicing of the cytochrome P-450 4A1 mRNA in both infant and adult kidney. The splicing of cytochrome P-450 4A2 mRNA is a novel finding. The splicing of cytochrome P-450 4A2 mRNA only occurred in adult kidney, suggesting that it is developmentally regulated. In both cytochrome P-450 4A1 and 4A2 isoforms, splicing occurs in downstream, untranslated regions. This alternative splicing may be relevant to tissue- and age-specific regulation of the expression of the gene (Ref. 7 and this study).
GF-109203X, which is a highly specific PKC inhibitor (33), abolished the effects of AA, 20-HETE, and 12(S)-HETE on the activity of PCT Na+-K+-ATPase. The lipoxygenase metabolite 12(S)-HETE enhanced PKC-induced phosphorylation of Na+-K+-ATPase at physiological Ca2+ concentrations. Taken together, these data indicate that lipoxygenase products of AA inhibit PCT Na+-K+-ATPase via PKC activation.
In conclusion, the AA metabolic pathways modulating renal tubular Na+-K+-ATPase are developmentally regulated. We present here both physiology and molecular biology data that suggest that the pathways shift from a lipoxygenase-dependent pathway in infant kidney to a cytochrome P-450-dependent pathway in adult kidney. If this shift in the signaling pathways during ontogeny turns out to be a principle that is present in many tissues, the finding would be of general interest for the understanding of postnatal maturation. It will also be important to find out the physiological significance of present finding for regulation of sodium excretion.
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ACKNOWLEDGEMENTS |
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We thank Lill-Britt Svensson and Dr. Ann-Christine Eklöf for experimental assistance.
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FOOTNOTES |
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This study was supported by grants from the Swedish Foundation for International Cooperation in Research and Higher Education (to A. Aperia and S. Nowicki), the Swedish Medical Research Council, and the Märta and Gunnar V. Philipson Foundation (to A. Aperia).
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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: A. Aperia, Dept. of Woman and Child Health, Pediatric Unit, Astrid Lindgren Children's Hospital, Karolinska Hospital, S-171 76 Stockholm, Sweden (E-mail: aniap{at}child.ks.se).
Received 17 May 1999; accepted in final form 30 November 1999.
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