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Departments of 1 Biochemistry and 2 Cell Physiology, Institute of Cellular Signalling, University of Nijmegen, 6500 HB Nijmegen, The Netherlands
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ABSTRACT |
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Confluent
monolayers of immunodissected rabbit connecting tubule and cortical
collecting duct cells, cultured on permeable supports, were used to
study the effect of adenosine on net apical-to-basolateral Ca2+ transport. Apical, but not
basolateral, adenosine increased this transport dose dependently from
48 ± 3 to 110 ± 4 nmol · h
1 · cm
2.
Although a concomitant increase in cAMP formation suggested the
involvement of an A2 receptor, the
A2 agonist CGS-21680 did not
stimulate Ca2+ transport, while
readily increasing cAMP. By contrast, the
A1 agonist
N6-cyclopentyladenosine
(CPA) maximally stimulated Ca2+
transport without significantly affecting cAMP. Adenosine-stimulated transport was effectively inhibited by the
A1 antagonist
1,3-dipropyl-8-cyclopenthylxanthine but not the
A2 antagonist
3,7-dimethyl-1-propargylxanthine, providing additional evidence for the
involvement of an A1 receptor.
Both abolishment of the adenosine-induced transient increase in
intracellular Ca2+ concentration
by
1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid and downregulation of protein kinase C (PKC) by prolonged phorbol
ester treatment were without effect on adenosine-stimulated Ca2+ transport. The data presented
suggest that adenosine interacts with an apical
A1 receptor to stimulate
Ca2+ transport via a hitherto
unknown pathway that does not involve cAMP formation, PKC activation,
and/or Ca2+ mobilization.
connecting tubule; cortical collecting duct; calcium transport; A2 receptors; adenosine 3',5'-cyclic monophosphate
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INTRODUCTION |
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IN MANY TISSUES, adenosine is involved in autoregulatory mechanisms affecting, for example, cardiac rate, lipolysis, smooth muscle tone, hemodynamics, hormone and neurotransmitter release, and renal electrolyte transport (4, 17). These actions of adenosine are mediated by cell surface receptors, which are coupled to guanine nucleotide binding proteins (G proteins). At present, three types of adenosine receptors are known which activate different effector systems (13-15). First, the A1 receptor is linked to Gi to inhibit adenylyl cyclase (5, 13, 17, 21). In addition, binding of adenosine to A1 receptors can result in activation of phospholipase C, leading to an increase in intracellular Ca2+ concentration ([Ca2+]i) and protein kinase C (PKC) activity (1, 5, 9, 13, 20). Second, the A2 receptor acts through Gs to activate adenylyl cyclase, leading to an increase in cAMP (9, 17, 19, 21). Third, the A3 receptor is a novel receptor subtype, recently described in heart and nerve terminals (14). This latter receptor was demonstrated to inhibit adenylyl cyclase and to couple to phospholipase C.
In the kidney, adenosine is formed on the breakdown of adenosine nucleotides and extruded by the action of nucleoside transporters (8, 21). The presence of A1 and A2 receptors has been described in several segments of the nephron including glomeruli (17, 19), thick ascending limb of Henle's loop (6, 17), cortical collecting duct (1, 2, 17), and inner medullary collecting duct (17, 26, 27). Although the functional significance of A1 and A2 receptors in the distal part of the nephron is not clear, the ability of adenosine to regulate basal and hormone-stimulated cAMP production and to stimulate calcium and inositol phosphate turnover makes it a potentially important modulator of hormonally regulated solute and water transport in this part of the nephron (2). Recent studies using monolayers of A6 cells derived from the kidney of Xenopus laevis have implicated A1 receptors in the regulation of sodium transport (9, 12). At present, however, there is limited knowledge on the role of these receptors in mammalian kidney functioning.
The aim of the present study was to investigate the effect of
extracellular adenosine on Ca2+
reabsorption in the mammalian distal nephron. To this end, rabbit connecting tubule and cortical collecting duct cells were isolated by
immunodissection and subsequently grown to confluence on permeable supports. Previous studies have demonstrated that these monolayers retain many characteristics of the original epithelium, including 1
,25-dihydroxyvitamin D3-,
arginine vasopressin (AVP)-, and parathyroid hormone (PTH)-stimulated
Ca2+ reabsorption,
aldosterone-stimulated Na+
reabsorption, and K+ secretion (3,
23, 25). The data presented demonstrate that adenosine interacts with
apical A1 receptors to stimulate apical-to-basolateral Ca2+
transport.
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MATERIALS AND METHODS |
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Chemicals. Collagenase A and hyaluronidase were obtained from Boehringer (Mannheim, Germany). 1,3-Dipropyl-8-cyclopenthylxanthine (DPCPX), 3,7-dimethyl-1-propargylxanthine (DMPX), CGS-21680 hydrochloride (CGS-21680), and the phosphodiesterase inhibitor, Ro 20-1724, were purchased from Research Biochemical International (Natick, MA). Fura 2-acetoxymethyl ester (fura 2-AM), 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA)-AM, and Pluronic F-127 were from Molecular Probes (Eugene, OR). The cAMP assay system was from Amersham. Thapsigargin was obtained from LC Services (Woburn, MA). All other chemicals, including adenosine, N6-cyclopentyladenosine (CPA), AVP, bovine parathyroid hormone [bPTH-(1-34)], forskolin, and 8-BrcAMP were obtained from Sigma (St. Louis, MO).
Primary cultures of rabbit kidney cortical collecting system. Rabbit kidney connecting tubule and cortical collecting duct cells were immunodissected from kidney cortex of New Zealand White rabbits (±0.5 kg) with antibody R2G9 and set in primary culture on permeable supports (0.33 cm2; Costar, Cambridge, MA), as described in detail previously (3). The culture medium was a 1:1 mixture of Dulbecco's modified Eagle's medium and Ham's F-12 medium (DME/F12, GIBCO; Life Technologies, Paisley, UK) supplemented with 5% (vol/vol) decomplemented fetal calf serum, 50 µg/ml gentamicin, 10 µl/ml nonessential amino acids (GIBCO), 5 µg/ml insulin, 5 µg/ml transferrin, 50 nM hydrocortisone, 70 ng/ml prostaglandin E1, 50 nM Na2SeO3, and 5 pM triiodothyronine, equilibrated with 5% CO2-95% air at 37°C. All experiments were performed with confluent monolayers between 5 and 8 days after seeding the cells. Transepithelial potential difference and resistance were routinely checked before and after every experiment to confirm confluency and intactness of the monolayer.
Determination of transcellular
Ca2+
transport. Confluent monolayers of rabbit cortical
collecting system cells, grown on permeable filters, were washed twice
and preincubated in physiological salt solution (PSS) containing (in
mM) 140 NaCl, 2 KCl, 1 K2HPO4,
1 MgCl2, 1 CaCl2, 5 glucose, 5 L-alanine, 5 µM indometacin,
and 10 mM HEPES-Tris (pH 7.4) for 15 min at 37°C. Subsequently, the monolayers were incubated in PSS (100 µl apical and 600 µl
basolateral) for another 90 min to measure transepithelial
Ca2+ transport. Drugs and hormones
were added to either the apical or basolateral compartment, as
indicated in the text. Appropriate stocks (×1,000) of these
compounds were dissolved in ethanol or dimethyl sulfoxide. Identical
concentrations of solvent were used as controls. At the end of the
incubation period, 25-µl samples were removed in triplicate from the
apical compartment and assayed for
Ca2+, using a colorimetric assay
kit (Boehringer). Under these experimental conditions, net
apical-to-basolateral Ca2+ flux is
linear with time for at least 3 h (3).
Ca2+ reabsorption is expressed in
nmol · h
1 · cm
2.
Determination of intracellular cAMP accumulation. To assess the effects of hormones and drugs on intracellular cAMP accumulation, confluent monolayers were preincubated in PSS containing the phosphodiesterase inhibitor, Ro 20-1724 (100 µM), for 15 min at 37°C. 3-Isobutyl-1-methylxanthine was not used, since it was shown to act as an adenosine receptor antagonist (1, 22). Hormones and drugs were added to either the apical or basolateral compartment, as indicated in the text, and the monolayers were incubated in PSS/Ro 20-1724 for another 15 min. At 15 min, both the apical and basolateral medium were discarded, and the filter was excised and rapidly transferred to 500 µl 5% (wt/vol) trichloroacetic acid to terminate the generation of cAMP. After three cycles of freezing and thawing, samples were centrifuged at 12,000 g to remove precipitated material, and trichloroacetic acid was repeatedly extracted with water-saturated diethyl ether. cAMP was assayed by radioligand binding using a cAMP assay system from Amersham.
Measurements of the cytosolic free Ca2+ concentration. Cortical collecting system cells, grown to confluence on permeable transparent supports, were loaded with fura 2-AM in DME/F12 medium containing 10 µM fura 2-AM, 0.01% (wt/vol) Pluronic F-127, 0.5 mM probenicid, and 4% (vol/vol) decomplemented fetal calf serum for 60 min at 37°C. Subsequently, the monolayers were washed twice with PSS and transferred to a temperature-controlled (37°C) perfusion chamber placed on the stage of an inverted microscope (Nikon Diaphot, Tokyo, Japan). The apical and basolateral compartments were perfused separately with PSS by means of a gravity-controlled superfusion system. Apical and basolateral flow rates were set at 1 and 5 ml/min, respectively. Fluorescence measurements were performed with a long-working-distance objective (Fluor ×60, N.A. = 0.7; Nikon). Dynamic video imaging was carried out with the MagiCal system and TARDIS software provided by Joyce Loebl (Tyne and Wear, UK), as described previously (10, 11, 18, 25). The fluorescence emission ratio at 492 nm after excitation at 340 and 380 nm was monitored. The interframe interval between two ratio frames was 6.4 s. Because absolute Ca2+ concentrations were difficult to obtain, due to technical problems with ionomycin calibration, fluorescence ratios are reported as a measure of [Ca2+]i.
Statistics. In all experiments, the data are expressed as means ± SE. Overall statistical significance was determined by analysis of variance. In the case of significance (P < 0.05), individual groups were compared by contrast analysis according to Scheffé. P < 0.05 were considered significant.
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RESULTS |
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Effect of adenosine on
Ca2+ absorption
across rabbit cortical collecting system. Cultured
cells of the rabbit cortical collecting system, grown to confluence on
permeable supports and incubated in the absence of any stimulus,
exhibited a net apical-to-basolateral Ca2+ flux of 48 ± 3 nmol · h
1 · cm
2
(n = 50) (Fig.
1).
Ca2+ absorption was significantly
stimulated by 10 µM adenosine when added to the apical side (110 ± 4 nmol · h
1 · cm
2;
n = 30, P < 0.05),
whereas basolateral addition did not significantly affect
Ca2+ absorption (51 ± 2 nmol · h
1 · cm
2,
n = 6). The stimulatory effect of
adenosine was comparable to that of bPTH (100 nM, basolateral), AVP (10 nM, basolateral), the adenylyl cyclase activator forskolin (1 µM,
both sides), and the cell-permeable cAMP analog, 8-BrcAMP (100 µM,
both sides), which increased Ca2+
reabsorption to 204 ± 9, 239 ± 8, 217 ± 4, and 241 ± 7%, respectively (Fig. 1). Figure
2A shows
that apical adenosine stimulated transcellular Ca2+ transport in a dose-dependent
manner with an EC50 of 0.7 ± 0.2 µM, a threshold concentration of 10-100 nM, and a maximally
effective concentration of 10 µM.
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Characterization of receptor type involved in adenosine-stimulated Ca2+ absorption. As shown in Fig. 2B, addition of adenosine to the apical side of monolayers incubated in the presence of 100 µM Ro 20-1724 to inhibit cAMP breakdown resulted in a dose-dependent accumulation of intracellular cAMP. At 100 µM, the maximal concentration used in this study, adenosine increased cAMP to 314 ± 20%. This observation suggests the involvement of an A2 receptor. To further characterize the type of receptor involved in adenosine-stimulated Ca2+ transport, the effect of specific agonists and antagonists was tested. Addition of the A2 receptor agonist CGS-21680 to the apical compartment did not stimulate Ca2+ transport, unless added at a relatively high concentration of 100 µM. However, at this latter concentration, the A2 agonist produced only one-third of the maximal effect of adenosine (Fig. 3A). By contrast, the A1 receptor agonist CPA progressively increased Ca2+ transport to a maximum of 228 ± 8%.
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CGS-21680 increased cAMP formation dose dependently (Fig. 3B). Remarkably, comparison of Fig. 3, A and B, reveals that the effect of CGS-21680 on cAMP formation was already significant (150% over basal) at a concentration (10 µM) at which Ca2+ transport was not stimulated. By contrast, CPA, at concentrations at which it effectively stimulated Ca2+ reabsorption, only poorly (117 ± 8%, n = 3) increased cAMP. Moreover, the effect of CPA on cAMP accumulation appeared to be all but dose dependent. These observations suggest that cAMP is not the intracellular messenger involved in adenosine-stimulated Ca2+ absorption.
Figure 3 shows that CGS-21680 stimulates cAMP accumulation at least 10 times better than Ca2+ transport. Taking into account that the affinity of CGS-21680 for the A2 receptor is ~100 times higher than that for the A1 receptor (4), it is most likely that the stimulatory effect of 100 µM CGS-21680 on Ca2+ transport occurs through the A1 receptor.
To confirm that the stimulatory action of adenosine on Ca2+ absorption was mediated by an A1 receptor, additional experiments were performed in the presence of the specific A1 antagonist, DPCPX. As shown in Fig. 4, pretreatment of the monolayers with DPCPX (10 µM) completely inhibited the action of 3 µM adenosine. By contrast, the A2 antagonist DMPX did not affect the stimulatory effect of adenosine.
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As shown in Fig. 5A, apically added adenosine (10 µM) induced a transient increase in [Ca2+]i within seconds after the onset of stimulation. Removal of extracellular Ca2+ did not significantly affect the adenosine-induced [Ca2+]i response (data not shown). A similar Ca2+ transient increase was observed when the monolayers were perfused at the apical side with the A1 receptor agonist CPA (Fig. 5B). By contrast, the A2 agonist CGS-21680, added at a concentration of 100 µM at the apical side, did not evoke an increase in [Ca2+]i (Fig. 5C). Subsequent addition of 100 µM ATP to the basolateral side still induced an increase in [Ca2+]i, indicating the responsiveness of the cells. The adenosine-induced increase in [Ca2+]i confirms A1 receptor activation of phospholipase C, resulting in enhanced inositol 1,4,5-trisphosphate and diacylglycerol formation.
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It is well established that the A1 receptor is coupled to Gi to inhibit adenylyl cyclase activation (5, 13, 17, 21). To provide additional evidence for the presence of a functional A1 receptor, we investigated the effect of CPA on AVP-induced cAMP accumulation. Figure 6 clearly demonstrates that CPA (100 µM) indeed inhibits the increase in cAMP evoked by 1 nM AVP.
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In view of the above finding that the stimulatory effect of adenosine
on Ca2+ transport is not
paralleled by an increase in cAMP formation, it was tested whether the
transient rise in
[Ca2+]i
and/or the increase in PKC activity mediate
adenosine-stimulated Ca2+
absorption. To this end, monolayers were cultured in the presence of
the phorbol ester
12-O-tetradecanoylphorbol 13-acetate
(TPA, 0.1 µM) for 5 days to downregulate PKC (24), after which the effect of adenosine on Ca2+
absorption was determined. Adenosine-stimulated
Ca2+ transport in
PKC-downregulated cells occurred with an equal potency as in untreated
monolayers (81 ± 4 vs. 88 ± 3 nmol · h
1 · cm
2;
n = 3) (Fig.
7). Buffering
[Ca2+]i
by loading the cells with 15 µM BAPTA-AM abolished the
adenosine-induced transient increase in
[Ca2+]i
but had no effect on the stimulatory action of adenosine on Ca2+ absorption (102 ± 2 vs.
99 ± 3 nmol · h
1 · cm
2)
(Fig. 8). On the other hand, increasing of
[Ca2+]i
by addition of the inhibitor of intracellular
Ca2+-ATPase activity, thapsigargin
(11, 16), did not affect the basal rate of
Ca2+ reabsorption (49.3 ± 2.7 vs. 45.3 ± 2.6 nmol · h
1 · cm
2;
n = 9, for control and
thapsigargin-treated monolayers, respectively). Taken together, these
results suggest that adenosine-stimulated Ca2+ transport is not mediated by
a downregulatable PKC isotype or transient elevation of
[Ca2+]i.
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To investigate the relationship between the classic cAMP-mediated pathway and the novel cAMP-independent pathway, we investigated the stimulatory effect of CPA and 8-BrcAMP, alone and in combination, on Ca2+ transport. Combination of maximally effective doses of both stimulants did not further increase the rate of Ca2+ transport. The most likely explanation is that the activity of one of the Ca2+ transporters is rate limiting. However, half maximally effective doses of CPA (3 µM) and 8-BrcAMP (3 µM) were clearly additive (Fig. 9). Because CPA, even in the presence of an inhibitor of cyclic nucleotide phosphodiesterase activity, only marginally increases cAMP (Fig. 3B), this additivity convincingly demonstrates that CPA acts through a separate cAMP-independent pathway and that this pathway and the cAMP-dependent pathway converge distally to stimulate Ca2+ transport.
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DISCUSSION |
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The present study demonstrates that adenosine stimulates Ca2+ reabsorption in primary cultures of the rabbit cortical collecting system via an apical A1 receptor. This conclusion is based on the following observations: 1) stimulation of Ca2+ transport was only observed on apical addition of adenosine; 2) the selective A1 agonist CPA stimulated Ca2+ reabsorption at least 100 times more potently than the selective A2 agonist CGS-21680; 3) adenosine-stimulated Ca2+ transport was completely inhibited by the selective A1 antagonist DPCPX and not by the selective A2 antagonist DMPX; 4) both CPA and adenosine, but not CGS-21680, induced an extracellular Ca2+-independent transient rise in [Ca2+]i, which is typical for A1 receptor activation; 5) CPA effectively inhibited AVP-induced cAMP accumulation, which implies the action of a Gi-coupled A1 receptor (5, 13, 17, 21); and 6) the minimal effective concentration achieved with adenosine was 10-100 nM, which is in agreement with previously published values for the A1 receptor (7).
The presence of adenosine receptors in the cortical collecting tubule, which forms part of the cortical collecting system used in the present study, has been demonstrated by Arend and co-workers (1, 2). At present, the functional relevance of these receptors is largely unknown. We now show, however, that apical adenosine receptors may play a regulatory role in Ca2+ homeostasis in the distal nephron. In the kidney, adenosine is produced on breakdown of adenosine nucleotides and transported to the lumen by the action of nucleoside transporters demonstrated to be present in proximal tubules, connecting tubules, and cortical collecting ducts (8, 21). Using monolayers of amphibian kidney A6 cells, Hayslett et al. (9) and Lang et al. (12) provided evidence for the involvement of adenosine receptors in the regulation of Na+ transport. It remains, however, to be elucidated whether this is also the case in the mammalian kidney.
It is generally accepted that transepithelial Ca2+ transport is triggered by an increase in cAMP, as classically observed with parathyroid hormone (3). However, the present study provides evidence that Ca2+ transport can be stimulated in a cAMP-independent manner. First, the A1 agonist CPA stimulated Ca2+ transport at concentrations at which it did not increase cAMP. Second, the selective A2 agonist CGS-21680 increased cAMP without affecting Ca2+ transport. This lack of effect of CGS-21680 on Ca2+ reabsorption is explained by the fact that, even in the presence of the cyclic nucleotide phosphodiesterase inhibitor, the increase in cAMP is marginal compared with that evoked by AVP (compare Figs. 3B and 6) and apparently does not exceed the threshold for Ca2+ transport. Further evidence that adenosine does not primarily act through cAMP comes from the observation that, at 1 µM, it markedly stimulated Ca2+ transport while increasing cAMP to a level (150% over basal) at which no Ca2+ transport was observed in the case of 10 µM CGS-21680. Together with the finding that both 8-BrcAMP and forskolin effectively stimulated Ca2+ reabsorption, representing the classic cAMP-dependent pathway, this suggests that cortical collecting system cells possess a separate cAMP-independent pathway leading to increased Ca2+ reabsorption. This idea is further supported by the fact that the stimulatory effects of CPA and 8-BrcAMP were additive.
Although the primary cell culture used in this study is heterogenous by nature and consists of at least three cell types, designated connecting tubules and principal and intercalating cells, we have previously demonstrated that the majority (±80%) of the cultured cells are calbindin-D28K positive and therefore involved in transepithelial Ca2+ transport (25). In addition, the present finding that adenosine and CPA increase [Ca2+]i in at least 80% of the individually analyzed cells suggests the functional presence of A1 receptors on the majority of the calbindin-D28K-containing cells.
In an attempt to elucidate the nature of the cAMP-independent pathway, we investigated whether the transient increase in [Ca2+]i and/or the activation of PKC in response to A1 receptor activation are involved in the stimulatory action of adenosine in Ca2+ reabsorption. Downregulation of PKC by prolonged (120 h) exposure to TPA did not affect adenosine-stimulated Ca2+ reabsorption. This finding suggests that PKC isotypes, sensitive to downregulation, are not involved in the mechanism of action of adenosine. The involvement of the transient increase in [Ca2+]i was excluded by the observation that adenosine-stimulated Ca2+ transport was not affected in monolayers loaded with the calcium chelator BAPTA. Alternatively, increasing [Ca2+]i by means of the selective inhibitor of endoplasmic reticulum Ca2+-ATPase activity, thapsigargin (1 µM), did not alter basal Ca2+ reabsorption. Taken together, these findings suggest that neither PKC nor [Ca2+]i represent the cAMP-independent pathway used by adenosine to stimulate Ca2+ reabsorption in this nephron segment.
In conclusion, our study provides evidence for the presence of an apical A1 receptor coupled to a hitherto unknown cAMP-independent pathway to stimulate apical-to-basolateral Ca2+ transport in cultured cortical collecting system cells. In terms of kidney physiology, adenosine may act as an autacoid to stimulate Ca2+ reabsorption in conjunction with circulating hormones.
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ACKNOWLEDGEMENTS |
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We thank M. de Jong for maintaining the primary cultures.
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FOOTNOTES |
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A. Hartog has been supported by the Dutch Kidney Foundation (no. C94.1348), and the research of P. H. G. M. Willems has been made possible by a fellowship of the Royal Netherlands Academy of Arts and Sciences.
Address for reprint requests: J. G. J. Hoenderop, 160 Biochemistry and Cell Physiology, Institute of Cellular Signalling, Univ. of Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
Received 23 July 1997; accepted in final form 8 January 1998.
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