1 Department of Medicine, McMaster University, Hamilton, Ontario L8N 1Y2; and 2 University of Toronto, Toronto, Ontario, Canada M55 1A8
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ABSTRACT |
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Mesangial cells (MC), grown on
extracellular matrix (ECM) protein-coated plates and stretched,
proliferate and produce ECM, recapitulating in vivo responses to
increased glomerular capillary pressure (Pgc). Transduction of strain
involves mitogen-activated protein kinases (MAPK), and we have shown
that p38 MAPK is activated by strain in MC. Because in vivo studies
show that nitric oxide (NO) in the remnant kidney limits glomerular
injury without reducing Pgc, we studied whether NO attenuated
stretch-induced p38 activation in MC. Increasing p38 activation
occurred with increasing stretch, maximally at 10 min at 27-kPa
vacuum. Cyclic strain increased nuclear translocation of phosphorylated
p38 by immunofluorescent microscopy and nuclear protein binding to
nuclear factor-
B (NF-
B) consensus sequences by mobility shift
assay. Both events were largely abrogated by the p38 inhibitor
SB-203580. The NO donors 3-morpholinosydnonimine,
S-nitroso-N-acetylpenicillamine, and 8-bromoguanosine 3',5'-cyclic monophosphate, a stable cGMP analog, prevented p38 activation and nulcear translocation. Thus strain induces
p38 activity and translocation to the nucleus and p38-dependent increases in nuclear protein binding to NF-
B. This pathway is attenuated by the NO donors or a cGMP analog.
nuclear factor-B; kidney glomerulus; physical forces; mitogen-activated protein kinases; signaling
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INTRODUCTION |
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IN THE GLOMERULUS, mesangial cells (MC) serve as architectural support for capillary loops and consequently experience pulsatile stretch-relaxation (1). Little resident glomerular cell proliferation or sclerosis is demonstrable in normal animals (14). However, models of glomerular sclerosis can be generated by maneuvers increasing intraglomerular pressure (Pgc) by 10 mmHg (4, 9, 10). Moreover, in these models, maneuvers that decrease Pgc attenuate sclerosis, further implicating mechanical stress in glomerular injury (2, 10, 24). Our laboratory and others have demonstrated protection against sclerosis and MC proliferation in remnant glomeruli by oral L-arginine supplementation to increase nitric oxide (NO) production (18, 29). L-arginine increases NO production by the remnant kidney and reduces glomerular endothelin-1 expression but does not lower glomerular capillary pressure (18).
The effects of mechanical forces on MC in vitro have been studied by culturing cells in wells with deformable bottoms and applying vacuum to the well to generate alternating cycles of strain and relaxation. Initial experiments using this methodology showed increases in cellular calcium entry and total protein kinase C (PKC) activity within 5 min of the application of strain to MC (1), followed by induction of mRNA for the protooncogene and activator protein-1 transcription factor component c-fos at 30 min (1). This effect was blocked by PKC inhibition (1). Subsequently, increases in both MC proliferation (14) and collagenous and noncollagenous extracellular matrix (ECM) protein synthesis were observed by 48 h, the sine qua non of sclerotic injury (30, 37).
Our laboratory and others have studied the link between early events
such as PKC activation and induction of transcription of
c-fos in stressed MC (15, 19,
21). We demonstrated increases in p44/42 and p38
mitogen-activated protein kinases (MAPK) signaling in response to
cyclic strain (19). Other investigators have found p38
MAPK activation in response to mechanical stress in cardiac myocytes
(22) and in isolated hearts perfused at high pressure
(7). Transfection of the specific upstream activators of
p38 MAPK at the MAP kinase kinase level (MKK3 and MKK6) led to
cardiomyocyte hypertrophy and protection from apoptosis
(34). Although nuclear factor-B (NF-
B)
transactivational activity has not been studied in response to
mechanical strain, it is seen in response to p38 MAPK activation by
constitutively active MKK6 (39), and in response to the
traditional p38 MAPK stimuli of hyperosmolarity (31) and
cytokines such as tumor necrosis factor (32). NF-
B
increases the expression of genes such as nitric oxide synthase (NOS)
(3) and cyclooxygenase 2 (COX-2) (11) in MC,
which are implicated in responses to intraglomerular hypertension. The
effects of NO on mechanical strain-induced MC signaling have not been elucidated.
We hypothesized that NO would limit MC signaling in response to
mechanical strain. Accordingly, we first sought to further characterize
p38 MAPK activation in response to cyclic mechanical strain in MC and
to link p38 MAPK activation to increased nuclear protein binding to
NF-B consensus sequences. We then studied the effect of NO on
mechanical strain-induced p38 MAPK activation and nuclear translocation.
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METHODS |
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Cell culture. Sprague-Dawley rat MC were cultured in DMEM supplemented with 20% FCS (GIBCO-BRL), streptomycin (100 µg/ml), penicillin (100 U/ml), and 2 mM glutamine at 37°C in 95% air-5% CO2. Experiments were carried out in cells between passages 15 and 20.
Application of strain-relaxation.
MC (2 × 106/well) were plated on to six well plates
with flexible bottoms coated with bovine type I collagen (Flexcell
International, McKeesport, PA). Cells were grown to confluence for
72 h, then rendered quiescent by incubation for 24 h in DMEM
with 0.5% FCS. To characterize the time of maximum response, cells
were initially exposed to cycles of strain-relaxation, generated by a
cyclic vacuum produced by a computer-driven system (Flexercell Strain Unit 2000, Flexcell), for periods of 2, 5, 10, 30, and 60 min. Plates
were exposed to continuous cycles of strain-relaxation, with each cycle
comprising 0.5 s of strain and 0.5 s of relaxation, for a
total of 60 cycles/min. Initially, vacuum pressures used were 10 to
27 kPa, inducing a 16-27% elongation in the diameter of the
surface. Subsequent experiments were performed at the time and strain
level of maximal response, 10 min and
27 kPa, respectively.
Protein isolation.
Cellular levels of p38 MAPK protein were determined in stretched and
unstretched control cells at the indicated times and vacuum levels
after the application of strain. Briefly, at the end of each strain
protocol, media was removed and the cells were washed once with
ice-cold PBS. PBS was then removed, and cells were harvested under
nondenaturing conditions on ice by incubation for 5 min with 70 ml
ice-cold cell lysis buffer/well [(in mM) 20 Tris (pH 7.4), 150 NaCl, 1 EDTA, 1 EGTA, 2.5 Na pyrophosphate, 1 -glycerophosphate, and 1 Na
orthovanadate, as well as 1% Triton X-100 and 1 µg/ml
leupeptin] and 1 mM phenylmethylsulfonyl fluoride (PMSF).
Cells were then scraped into microcentrifuge tubes on ice and sonicated
four times for 5 s each. After microcentrifugation at 14,000 rpm
for 10 min at 4°C, the supernatant was transferred to a fresh
microcentrifuge tube. Protein concentration was measured with the
Bio-Rad assay kit (Bio-Rad, Mississauga, ON).
Western blotting for p38 MAPK. Forty micrograms of sample were then separated on a 10% SDS-PAGE gel. After electroblotting to a nitrocellulose membrane (Protran, Schleicher and Schuell, Keene, NH), membranes were incubated for 3 h at room temperature with 25 ml of blocking buffer [1× Tris-buffered saline (TBS), 0.1% Tween-20 with 5% wt/vol nonfat dry milk] and then overnight at 4°C with p38 MAPK polyclonal antibody (1:1,000, New England Biolaboratories, Beverly, MA) in 10 ml of antibody dilution buffer (1× TBS, 0.05% Tween-20 with 5% BSA) with gentle rocking. Membranes were then washed three times with 1× TBS with 0.1% Tween-20 (TTBS) and then incubated with horseradish peroxidase-conjugated anti-rabbit secondary antibody (1:2,000) in 10 ml of blocking buffer for 45 min at room temperature. After three further TBS washes, the membrane was incubated with LumiGlo reagent (KPL, Gaithersburg, MD) and then exposed to X-ray film (X-OMAT, Kodak, Rochester NY).
p38 MAPK kinase assay. After protein isolation from total cell lysate as above, 200 µg total protein were then incubated with phospho-p38 MAPK antibody (Thr180/Tyr182) immobilized on protein sepharose A beads (1:100; New England Biolaboratories) with gentle rocking overnight at 4°C. Lysate was then microcentrifuged for 30 s at 14,000 rpm to recover the beads, and the pellet was washed twice with 0.5 ml of 1× lysis buffer.
For the kinase assay, after immunoprecipitation, pellets were washed twice with 0.5 ml kinase buffer [(in mM) 25 Tris, 5Immunofluorescent microscopy of p38 MAPK translocation.
After each strain protocol, cells were washed three times with PBS and
fixed with 3.7% formaldehyde (300 µl/well) for 10 min at room
temperature. Cells were washed three times with PBS and then
permeabilized in 100% methanol for 5 min at 20°C, washed again
with PBS, and incubated with anti-phospho-p38 MAPK
(Thr180/Tyr182; New England Biolaboratories)
1:25 in PBS (after the primary antibody had been centrifuged at 12,000 rpm for 2 min and the supernatant was recovered) for 30 min at room
temperature. Cells were washed three times in PBS and incubated with a
secondary goat anti-rabbit green fluorescent-conjugated antibody
(Alexis Biochemicals) 1:50 in PBS for 30 min at room temperature in the dark. Cells were washed and then mounted by removing the flexible base
from each well and placing it directly on a glass slide, using one drop
of antifade mount media (Slow Fade, Molecular Probes, Eugene, OR). A
drop of mount media was then placed on top of the cells, which were
then covered with a glass slip. Slides were stored at 4°C in the dark
until confocal laser scanning microscopy was performed by using a
Bio-Rad MRC-600 confocal microscope (Bio-Rad) within 10 days. To
demonstrate phospho-p38 MAPK translocation in response to osmotic
stress, MC were exposed to 400 mM sorbitol for 30 min and then were
analyzed as above.
Nuclear protein binding to NF-B consensus sequences.
These experiments were performed according to published methods
(23, 26). After washing in cold PBS, nuclear
extracts of MC stretched at
27 kPa for 10 min were prepared by lysis
in hypotonic buffer [(in mM) 20 HEPES, pH 7.9, 1 EDTA, 1 EGTA, 20 NaF,
1 Na3VO4, 1 Na4P2O7, 1 DTT, and 0.5 PMSF, as
well as 1 µg/ml aprotinin, 1 µg/ml leupeptin, 1 µg/ml pepstatin
A, and 0.6% Nonidet P-40], homogenized, and sedimented at 16,000 g for 20 min at 4°C. Pelleted nuclei were resuspended in
hypertonic buffer with 0.42 mol/l of NaCl2 and 20%
glycerol and rotated for 30 min at 4°C. After centrifugation for 20 min at 16,000 g, the supernatant was collected and protein
concentration was measured with the Bio-Rad assay kit.
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RESULTS |
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Characterization of strain-induced p38 MAPK activity in MC.
The first purpose of the present study was to determine the time and
magnitude of strain dependence of p38 MAPK activation in MC. MC lysates
were initially subjected to Western blot analysis of p38 MAPK
expression, and subsequently analysis of p38 MAPK activity was
performed by determination of the phosphorylation of an ATF-2 fusion
protein by MC lysates. Cultures were exposed to strain for periods of
2, 5, 10 , 30, and 60 min at vacuum levels of 10,
14,
18,
22,
and
27 kPa. Unstretched MC on identical plates were used as the
control. Representative autoradiographs are shown in Figs.
1 and 2.
In Fig. 1 the time course was explored as MC were stretched at
27 kPa
for the times indicated above. No changes in the protein expression of
p38 MAPK were observed (top). However, changes were seen in
p38 MAPK activity at 2 min, reaching a maximum at 10 min and returning
to baseline by 30 min (middle). The data from four
consecutive separate experiments are graphically presented with SD bars
(bottom). Activity at 5 and 10 min was different from
unstretched baseline (P < 0.05, n = 4). In Fig. 2, dependence on the magnitude of strain was studied, as MC
were exposed to the levels of vacuum outlined above for 10 min. Again,
no changes in the protein expression of p38 MAPK were observed
(top). In contrast, activity is increased at all strain
levels and increases with increasing stretch (middle). The
data from four consecutive experiments are graphically presented with
SD bars, and activity at all levels of strain is different from
baseline (P < 0.05, n = 4 experiments;
bottom).
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Inhibition by SB-203580.
To determine the concentration of SB-203580 required to inhibit p38
MAPK activity, we used 400 mM sorbitol, an osmotic stimulus for p38
MAPK activation. Figure 3 shows markedly
increased p38 MAPK activity after 10 min of 400 mM sorbitol was added
to MC grown on flexible-bottom coated plates. Inhibition was seen with SB-203580 concentrations of 50 µM and above. Consequently, the concentration of 50 µM was used for subsequent experiments.
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Immunofluorescent microscopy of p38 MAPK translocation.
The nuclear translocation of active (phosphorylated) p38 MAPK induced
by strain was studied by confocal microscopy, and representative photomicrographs are shown in Fig. 4. As
shown in Fig. 4A, little phosphorylated p38 MAPK is
identified by the primary antibody in unstretched MC, and the
phospho-p38 MAPK present is primarily cytoplasmic in location. The
addition of 400 mM sorbitol for 30 min to MC as an osmotic stress led
to prompt nuclear translocation of phospho-p38 MAPK (B).
Stretched MC (10 min, 60 Hz, 27 kPa) grown on type I collagen-coated
plates but pretreated with 50 µM SB-203580 also show little
phospho-p38 translocation (C). However, prompt induction and
nuclear translocation of phospho-p38 MAPK are shown in response to 10 min of cyclic strain of
27kPa in the absence of inhibitor
(D).
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Nuclear protein binding to NF-B consensus sequences.
We next sought to determine whether downstream intranuclear events were
affected by strain and the consequent activation of p38 MAPK by
assessing the binding of nuclear protein to NF-
B consensus
sequences. Binding was studied from the time of maximal response (10 min) and at 30 and 60 min of strain to allow for downstream propagation
of the signal. SB-203580 (50 µM) was added 10 min before strain
protocols in one-half of the experiments.
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Effect of SNAP, SIN-1, and cGMP on strain-induced p38 MAPK
signaling.
To study the effect of NO on p38 MAPK activation in response to strain,
either 70 µM SNAP, 100 µM and 1 mM SIN-1, or 1 mM 8-BrcGMP was
added 10 min before the initiation of stretch protocols. Figure
6 shows that the increase in p38 MAPK
activity seen with 10 min of cyclic strain could be completely
inhibited with 70 µM SNAP (middle). The data from four
consecutive separate experiments are graphically presented with SD bars
(bottom). The inhibition at 10 min by SNAP was significant
(P < 0.05, n = 4). Figure
7 shows that the increase in p38 MAPK
activity seen with 10 min of cyclic strain could also be completely
inhibited with another NO donor, SIN-1, and that the inhibition was
independent of dose. Inhibition with 100 µM SIN-1 (top)
and 1 mM SIN-1 (bottom) is shown. The data from four
consecutive separate experiments at each dose are graphically presented
with SD bars (bottom). The inhibition at 10 min by either
100 µM or 1 mM SIN-1 was significant (P < 0.05, n = 4). Figure 8 shows
that the effect of the NO donors can be reproduced, in part, by a
stable cGMP analog, as 8-BrcGMP also significantly inhibited the p38
MAPK activity seen at 10 min in response to strain (middle).
Inhibition was not complete, however, as with SNAP or SIN-1. The data
from four consecutive separate experiments are graphically presented
with SD bars (bottom). The inhibition at 10 min by 8-BrcGMP
was significant (P < 0.05, n = 4).
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DISCUSSION |
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Considerable evidence supports the conclusion that increased physical force (which may be as little as a 20% increase in capillary pressure) triggers MC responses that ultimately contribute to the development of glomerulosclerosis (30, 37, 38) In vitro studies of the application of cyclic mechanical strain to MC have demonstrated that this stimulus results in the production of collagenous proteins (14) and fibronectin (15). MC proliferation has also been observed in response to strain (13, 14, 20).
Our laboratory (19) and others have studied how the
mechanical signal is transduced in MC. The first site of transduction occurs at the cell membrane. Initial studies of mechanical strain in MC
generally used increased expression of the protooncogene c-fos
to study manipulations that might ultimately impact ECM protein
synthesis and cell proliferation (1). Downregulation of
PKC was shown to attenuate the c-fos expression induced by strain (13), as was calcium chelation by EGTA
(13). Other membrane-associated events have also been
implicated. For example, in MC, strain-induced transforming growth
factor- expression is tyrosine kinase dependent (15).
The proliferative effects of mechanical strain are to some extent
matrix dependent. Cells adherent to fibronectin show the greatest
strain-induced proliferative response, and this is inhibited by
coincubation with RGD peptides (35). Integrin-focal
adhesion complex interactions have been studied, and tyrosine
phosphorylation of the focal adhesion associated kinase
pp125FAK is seen in stretched MC (12).
Signaling of mechanical stimuli to the cell nucleus after membrane events involves the ubiquitous MAP kinase cascades. Each of the MAP kinase cascades consists of three protein kinases acting sequentially: a MKK, a MAP kinase activator, and a MAP kinase (8).
Our laboratory has reported that cyclic mechanical strain increases p38
MAPK activation and [3H]thymidine uptake in primary
cultured MC adherent to collagen I (19). The first goal of
the present study was to more fully characterize the time course of p38
MAPK activation and the dependence of p38 MAPK activation on the
magnitude of stretch in MC exposed to cyclic strain. Cyclic strain, at
a frequency of 60 Hz, led to an earlier increase in p38 MAPK activation
than we originally reported. Basal p38 MAPK activity was low in static
MC, but an increase in p38 MAPK activity was evident as early as 2 min
after the application of strain, and peaked at 10 min. We also observed that p38 MAPK activity was dependent on the magnitude of stretch. Stretch-induced activation of p38 MAPK was accompanied by translocation of phospho-p38 MAPK into MC nuclei. Although the classic stimuli for
p38 MAPK activation include hyperosmolality (19) and
proinflammatory cytokines, such as interleukin-1 (16),
a link between a physical force and cellular p38 MAPK activation has
also been reported in cardiac myocytes after aortic constriction
(34). When cardiac myocytes are exposed to strain in
vitro, both extracellular signal-regulated kinase (ERK) and
p38 MAPK activation have also been observed (22). More
recently, King and co-workers (17) have reported that high glucose concentrations also activate p38 MAPK in MC. Mechanical strain,
therefore, appears to activate what has heretofore been considered an
"inflammation" pathway in cardiac myocytes and MC.
Because p38 MAPK has been implicated in the signaling pathways of
proinflammatory cytokines and the cytokine-induced nuclear factor
NF-B, the second goal of the present study was to determine whether
cyclic mechanical strain led to a p38 MAPK- dependent increase in
nuclear protein binding to NF-
B in MC. We observed that cyclic
stretch increased nuclear protein binding to NF-
B in MC, and the
increase was largely abrogated by inhibiting p38 MAPK activity with
SB-203580. Although we did not link nuclear protein binding to NF-
B
to transcriptional activation in our study, Akai and co-workers
(1) have reported that cyclic stretch-relaxation induces
COX-2 synthesis. COX-2 expression is regulated transcriptionally by
NF-
B (3, 36), and it is tempting to
speculate that mechanical strain induces COX-2 expression via p38 MAPK
activation and NF-
B.
Our laboratory (18) and others (29) have shown that dietary supplementation with L-arginine, a NO donor, limits glomerular injury in the remnant kidney. L-arginine increases NO production by the remnant kidney but does not lower glomerular capillary pressure. Therefore, the third goal of the present study was to determine whether a NO donor would attenuate stretch-induced MC signaling, and specifically, whether NO would limit stretch-induced p38 MAPK activation. We first observed that the NO donor SNAP attenuated stretch-induced p38 MAPK activation in MC. Because NO can influence the activity of intracellular proteins by activating guanylate cyclase and increasing cGMP or by increasing the posttranslational modification of proteins via S-nitrosylation, we compared the effect of the NO donor SNAP to the effect of an active but stable cGMP analog, 8-BrcGMP, on stretch-induced p38 MAPK activation. Like SNAP, 8-BrcGMP also attenuated the activation of p38 MAPK by stretch in MC. Moreover, both SNAP and 8-BrcGMP prevented the nuclear translocation of phospho-p38 MAPK.
NO may be generated by constitutive enzymes [such as endothelial NOS (eNOS)] or by enzymes induced by inflammatory events [inducible NOS (iNOS)] (25). The concentration of NO donors that corresponds to levels of NO in vivo produced by each of these enzymes is uncertain. Chiu and co-workers (6) have found that SNAP at either 100 or 400 µM inhibits shear stress-induced p44/42 ERK activity in endothelia. A NOS inhibitor increased shear-induced p44/42 activity. As shear should not induce iNOS, it was postulated that eNOS events were being modeled (6). Studies of MC have generally used 1 mM concentrations of NO donors to mimic iNOS effects (5, 28). Accordingly, we used another NO donor, SIN-1, to ensure that p38 MAPK inhibition was not specific to SNAP or dose dependent. We observed that SIN-1 at either 100 µM or 1 mM also abrogated stretch-induced p38 MAPK activity.
We did not determine the mechanism responsible for the effect of NO on stretch-induced p38 MAPK activation, but interestingly, NO provided as SNAP inhibits the angiotensin II induction of ERK signaling by preventing the calcium-sensitive phosphorylation of proline-rich tyrosine kinase 2 (PYK2) (33). The activation of p38 MAPK by osmotic stress (sorbitol) has very recently been shown to be PYK2 dependent (27). Because PYK2 serves to phosphorylate pp125FAK in response to integrin-mediated signaling, it is quite plausible that p38 MAPK activation in response to mechanical strain and the inhibition by NO donors is mediated at this level. Further studies will be necessary to test this hypothesis.
In conclusion, these studies reveal cross-talk between mechanical
strain-induced MC signaling and NO signaling and suggest parallels
between mechanical strain and cytokine signaling. Cyclic strain leads
to a rapid activation of p38 MAPK in MC. This activation is accompanied
by translocation of phospho-p38 MAPK to the MC nucleus and a p38
MAPK-dependent increase in NF-B binding, thus linking physical
forces to the regulation of gene expression usually implicated in
inflammation. This signaling pathway can be inhibited by NO donors and
a stable cGMP analog.
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ACKNOWLEDGEMENTS |
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This work was supported by a grant from the Heart and Stroke Foundation of Canada and the Juvenile Diabetes Foundation/Medical Research Council of Canada (to J. W. Scholey) and from the Kidney Foundation of Canada (to A. J. Ingram). J. W. Scholey was also supported by a Scholarship Award from the Pharmaceutical Manufacturers' Association of Canada/Medical Research Council.
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FOOTNOTES |
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Address for reprint requests and other correspondence: A. J. Ingram, 500-25 Charlton Ave. East, Hamilton, Ontario, Canada L8N 1Y2 (E-mail: ingrama{at}fhs.mcmaster.ca).
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.
Received 13 September 1999; accepted in final form 29 March 2000.
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