(Hypertension. 2001;37:1171.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Activation of NF-
B in Tubular Epithelial Cells of Rats With Intense Proteinuria
Role of Angiotensin II and Endothelin-1
From the Renal and Vascular Research Laboratory (D.G.-G., R.L., N.T., J.E.), Department of Pathology (J.F., F.M.), Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain.
Correspondence to Jesús Egido, MD, Renal and Vascular Laboratory, Fundación Jiménez Díaz, Avda Reyes Católicos 2, 28040-Madrid, Spain. E-mail ehiper{at}fjd.es
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Abstract |
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Abstract—The mechanisms by which persistent proteinuria induces interstitial inflammation and fibrosis are not well known, although nuclear factor-
B (NF-B), which regulates the
transcription of many genes involved in renal injury, could be
implicated. In rats with intense proteinuria, we studied the renal
activation of NF-B as well as the potential involvement of the
vasoactive hormones angiotensin II (Ang II) and
endothelin-1 (ET-1). Uninephrectomized Wistar-Kyoto rats receiving 1
g/d of BSA had proteinuria but no renal morphological lesions at day 1.
By contrast, tubular atrophy and/or dilation and mononuclear cell
infiltration were observed after 8 or 28 days of BSA administration,
coinciding with maximal proteinuria. In relation to control
uninephrectomized rats, the renal cortex of nephritic rats showed an
increment in the activation of NF-B at all time periods studied. By
in situ Southwestern histochemistry, NF-B activity was mainly
localized in proximal tubules, interstitial mononuclear
cells, and, to a lesser extent, the glomeruli. The administration of
the ACE inhibitor quinapril plus the
ETA/ETB receptor
antagonist bosentan during 28 days to BSA-overloaded
animals diminished proteinuria, renal lesions, and NF-B activity
more markedly than single drugs. Cultured tubular epithelial cells
exposed to BSA revealed an intense NF-B activation in a time- and
dose-dependent manner. Incubation of cells with receptor
antagonists of Ang II (AT1:
losartan and AT2: PD-123,319) or ET-1
(ETA: BQ123 and ETB:
IRL1038) inhibited significantly the BSA-induced NF-B activity
(90%, 75%, 90%, and 60% of inhibition versus basal, respectively).
Our results show that overload proteinuria causes NF-B activation in
tubular epithelial cells both in vivo and in vitro. The vasoactive
peptides Ang II and ET-1 appear to be implicated in this effect. The
results reveal a novel mechanism of perpetuation of renal damage
induced by persistent proteinuria.
Key Words: proteinuria • epithelium • renal disease • angiotensin II • endothelin
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Introduction |
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Tubulointerstitial inflammation and the gradual deterioration of the renal function characterize progressive renal diseases.1 Several studies have demonstrated the importance of proinflammatory factors such as cytokines, adhesion molecules, growth factors, and vasoactive peptides in the progression of renal damage.1 2 Although the mechanisms leading to end-stage renal failure are not completely elucidated, persistent proteinuria is always considered an aggravating factor,1 suggesting that it could play a direct role in the development of renal injury.
The mechanisms by which proteinuria could cause interstitial inflammation and fibrosis are still not fully understood. In several experimental models of renal damage characterized by heavy and sustained proteinuria, the expression of vasoactive substances such as angiotensin II (Ang II) and endothelin-1 (ET-1) and chemokines such as monocyte chemoattractant protein-1, RANTES, and osteopontin was demonstrated in renal tissue.1 3 4 The incubation of cultured proximal tubular cells with different proteins, in concentrations found in the urine of patients with nephrotic syndrome, led to the activation of proinflammatory molecules.5 6 7
In vitro studies have demonstrated that the expression of
most of these factors is regulated by transcription factors, such as
nuclear factor B
(NF-B).6 7 8 9
In unstimulated cells, NF-B is present as an inactive dimer
bound to an inhibitory subunit (IB). Different
proinflammatory agents activate NF-B by releasing IB,
resulting in the passage of NF-B into the nucleus, where it binds to
specific sequences in the promoter regions of target
genes.10 NF-B has been
implicated in some inflammatory processes such as asthma and rheumatoid
arthritis (reviewed in Reference 1010 ). We have demonstrated that in a
model of accelerated atherosclerosis in rabbits, there
was an activation of NF-B in the arterial wall,
coinciding with an increase in the neointima formation and
the infiltration of inflammatory
cells.11 Proteinuria-induced
chemokine production in cultured proximal tubular cells is
mediated by
NF-B.6 7
In this work, we studied whether proteinuria can directly
activate NF-B in a rat model of renal injury induced by
protein overload and characterized by early and intense proteinuria
associated to tubulointerstitial
lesions.3 12 In
addition, we localized the NF-B activity in the rat kidney by in
situ Southwestern histochemistry, a technique that allows detection of
transcription factors in paraffin-embedded tissues, as recently
described by our
laboratory.13 Since we have
reported that intense proteinuria can induce the production of
Ang II and ET-1 in renal cortex of protein-overloaded
rats,3 4 we
approached the hypothesis that these vasoactive hormones could be
involved in NF-B activation induced by
albumin.
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Methods |
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Animal Model
Female Wistar rats (100 to 150 g) were fed standard rat chow ad libitum and given free access to water. Uninephrectomized (UNX) rats received daily injections of 1 g of BSA (Sigma) or saline.4 12
To assess the role of Ang II and ET-1 in the development of nephritis, we gave UNX animals daily injections of 1 or 0.5 g of BSA. After the first BSA injection, animals were treated with the ACE inhibitor quinapril (as powdered hydrochloride salt, Parke-Davis) and/or the ETA/ETB receptor antagonist bosentan (RO 47-0203; 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl]-benzene-sulfonamide, Hoffmann-La Roche Ltd). Quinapril (200 mg/L) was added to the drinking water and replaced every 48 hours, and bosentan (100 mg/kg in a dissolution of 5% arabic rubber) was given by gastric gavage once daily.
Periodically, all animals were housed in metabolic cages and 24-hour urine was collected for protein measurement.14 At the end of the studies, animals were anesthetized with sodium pentobarbital (5 mg/100 g body wt), and kidneys were perfused with cold sodium saline and removed.
Renal Histopathological Studies
For light microscopy, paraffin-embedded sections (4
µm thick) were prepared and stained with hematoxylin-eosin and
Masson’s trichrome. Glomerular (mesangial cell
proliferation and matrix expansion) and
tubulointerstitial injury (tubular dilation and/or
atrophy, interstitial fibrosis, and inflammatory cell
infiltrate) were graded by the following semiquantitative score: 0, no
changes; 1, focal changes that involve 25% of the sample; 2, changes
affecting >25% to 50%; 3, changes involving >50% to 75%; and 4,
lesions affecting >75%. Two independent observers performed the
semiquantification of morphological lesions in a blinded
fashion.
Cell Cultures
The cell line NRK 52E, derived from rat kidney
epithelial cells, was obtained from the American Type Culture
Collection (Rockville, Md). Cells were grown in DMEM (BioWhittaker)
supplemented with 5% fetal calf serum (Gibco BRL), 60 U/mL penicillin,
60 µg/mL streptomycin, and 2 mmol/L glutamine (BioWhittaker) at
37°C in the presence of 5% CO2. Cells were
used between the 7th and 12th passages. In each experiment, cells were
made quiescent for 48 hours in DMEM medium without fetal calf serum and
stimulated at different times with BSA, Ang II (Sigma), ET-1 (Peninsula
Laboratories), or phorbol 12-myristate 13-acetate (PMA, Sigma).
In some experiments, cells were preincubated with lysine (Sigma) for 1
hour to inhibit the cellular protein uptake at the brush border
membrane. In another group of experiments, cells were preincubated for
1 hour with two Ang II receptor antagonists:
AT1, losartan (Dupont Merck) and
AT2, PD-123,319 (RBI)
(10-6 mol/L); or with two ET receptor
antagonists: ETA, BQ123 and
ETB, IRL1038 (Neosystem)
(10-6 mol/L).
Extraction of Nuclear Proteins and
Electrophoretic Mobility Shift Assay Studies
Nuclear extracts from renal cortex and cells were
obtained as previously
reported.11 The protein
concentration of the extracts was quantified by the BCA method (Bio-Rad
Laboratories). Electrophoretic mobility shift assays (EMSA) were
performed with a commercial kit (Promega) as
described.13 For supershift
assays, 1 µg of anti-p50 or anti-p65 antibody (Santa Cruz
Biotechnology) was added and incubated for 1 hour before the addition
of the labeled probe.
Cellular Localization of NF-B
Activity
To localize the NF-B activity in the rat kidney,
in situ Southwestern histochemistry was performed on paraffin-embedded
renal tissue sections from UNX control and BSA-overloaded animals, as
previously described.13 For
negative controls, samples were incubated with a mutant NF-B probe
or with a 100-fold excess of unlabeled consensus
oligonucleotide. The number of cells positive to
NF-B activation in glomeruli (n=20 per biopsy) and in
tubulointerstitium (per x250 field, excluding glomeruli) was
quantified with computer-assisted image analysis software
(Optimas 6.5, Media Cybernetics) and digitized
images.
Statistical Analysis
Results are expressed as mean±SEM. Comparisons
between groups were made by unpaired Student’s
t test or the Kruskal-Wallis
nonparametric ANOVA test when appropriate. Differences were
taken as significant at
P<0.05.
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Results |
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Development of Nephritis
The administration of 1 g BSA to UNX rats induced a marked increment in the urine protein excretion (Figure 1A). By light microscopy (semiquantitative analysis) no significant renal morphological lesions were seen at day 1. However, animals receiving BSA during 8 and 28 days developed marked tubular lesions (atrophy, vacuolization, dilation, and casts), interstitial infiltration of mononuclear cells, and mesangial expansion (Figure 1, B through G).
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) and BSA-overloaded rats (•). Results are expressed as mean±SEM, n=12 animals per group. *P<0.05 vs UNX control rats at same time period. #P<0.05 vs BSA-overloaded rats at day 1. B through G, Histological lesions of UNX controls and BSA-overloaded rats on days 1, 8, and 28. B, Representative UNX control rat at day 8 without renal lesions. C, In BSA-overloaded rats at day 1, no renal morphological lesions were observed. However, animals receiving BSA during 8 days (D) and 28 days (E) developed marked tubulointerstitial lesions. Photographs are representative of 
7 animals from each group (magnification, x100). Glomerular (F) and tubulointerstitial (G) damage score of UNX control (white columns) and BSA-overloaded rats (black columns). Data represent mean±SEM, n=7 animals per group. *P<0.05 with respect to UNX control at same time. ND indicates nondetected.
Studies of NF-B Activation in Renal
Cortex
By EMSA studies, NF-B activity was increased in the
renal cortex of BSA-overloaded rats compared with that of UNX control
animals at all time periods studied. NF-B activity was increased at
day 1 and remained high up to day 28
(Figure 2, lanes 1 to 6). The maximal NF-B activation was
found at day 8 (2.3-fold versus UNX controls). The presence of a
100-fold excess of unlabeled NF-B oligonucleotide
(Figure 2, lane 7), or the lack of nuclear proteins in the
experiment (data not shown), inhibited the binding signal, confirming
the specificity of the assay. At day 8, in nephritic rats the NF-B
complex consisted of dimers containing p50 and p65 subunits, because
the preincubation for 1 hour with the respective antibodies reduced the
intensity of the complex
(Figure 2C). However, in rats with ureteral obstruction,
NF-B complexes containing subunit p65 were less prevalent than
complexes containing p50, p52,
c-Rel, or
RelB,15 whereas in rats with
immune complex nephritis, c-Rel
was not present in the activated
NF-B.16 Although these
data may suggest that the different composition of NF-B dimers could
be determinant in the expression of different genes, further studies
are needed in this regard.
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Cellular Localization of NF-B
Activation
In UNX control animals, NF-B activity was localized
in proximal tubules (8 days: 34±15 cells per field) and to a lesser
extent in glomeruli (0.23±0.02 cells per glomerulus, n=7). The
administration of BSA to UNX rats induced an increment in the number of
NF-B–positive cells both in tubules (24 hours: 135±30; 8 days:
194±33 cells per field;
P<0.05 in respect to UNX
control, n=7 per group) and glomeruli (24 hours: 37±18; 8 days: 51±14
cells per glomerulus; P<0.05
in respect to UNX control, n=7 per group)
(Figure 3, A and B). At 8 days, in BSA-overloaded animals,
renal interstitial cells (which were not detected either in
UNX controls or BSA-overloaded rats at 24 hours) also showed NF-B
activation (93±23 cells per field, n=7)
(Figure 3B). Neither the incubation of the sections with a
mutant NF-B probe (data not shown) nor with a 100-fold excess of
unlabeled consensus oligonucleotide
(Figure 3C) showed any positive staining, indicating the
specificity of the technique.
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Role of Ang II and ET-1 on Proteinuria,
Morphological Lesions, and NF-B Activation in Nephritic Rats
As mentioned above, rats receiving 1 g of BSA had
severe proteinuria and marked tubulointerstitial
lesions. In early experiments, these animals were treated with
quinapril or bosentan, as indicated in the Methods section. However, no
effect was noted either on proteinuria or on morphological lesions.
When both drugs were given in combination, a certain improvement was
noted, but only at day 8 (data not shown). Because of the severity of
the lesions observed, we performed new experiments, injecting a
half-dose of BSA (0.5 g/d). In these conditions, animals also showed
proteinuria and renal lesions, although less severe than those
displayed by 1 g BSA-overloaded animals
(Figure 1 and 4). The administration of quinapril during 28
days to UNX animals receiving 0.5 g BSA significantly reduced
proteinuria. By contrast, bosentan had no effect or a mild effect on
proteinuria. However, the combination of quinapril and bosentan reduced
proteinuria more markedly than quinapril alone
(Figure 4A). By light microscopy (semiquantitative
analysis), untreated rats showed important renal lesions
(interstitial infiltrate, tubular atrophy, protein casts
within the proximal and distal tubules, and mesangial
expansion and proliferation) that were significantly attenuated by
quinapril/bosentan treatment (0.6±0.1 versus untreated rats: 1.9±0.2;
P<0.01; n=7 per group) but not
by quinapril or bosentan alone, although a certain improvement was
noted (0.9±0.2 and 1.1±0.2, respectively;
P=NS; n=7 per group)
(Figure 4, B through E). As expected, 0.5 g
BSA-overloaded rats had increased NF-B activation compared with UNX
control rats, which was significantly decreased in quinapril-treated
and quinapril/bosentan-treated rats but not in bosentan-treated rats
(Figure 4, F and G).
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Effect of Albumin on NF-B Activation
in Cultured Tubular Epithelial Cells
As previously reported, albumin causes NF-B
activation in cultured tubular epithelial
cells.6 7 In our
experimental conditions, BSA overload (30 mg/mL) induced NF-B
activation in a time-dependent manner, being the maximal effect after
30 minutes of incubation
(Figure 5A). NF-B activation was already noted with 1
mg/mL BSA for 30 minutes
(Figure 5B). The preincubation of the cells with 100
mmol/L lysine inhibited the BSA-induced NF-B activity, indicating
that this effect was specific for BSA
(Figure 5B).
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Role of Ang II and ET-1 on the NF-B
Activation in Tubular Epithelial Cells
In parallel experiments, we detected by reverse
transcription–polymerase chain reaction that tubular epithelial cells
NRK 52E have a basal mRNA expression of both Ang II receptors
(AT1 and AT2) and ET-1
receptors (ETA and ETB)
(data not shown).
Cells were preincubated for 1 hour with losartan
(AT1 receptor antagonist),
PD-123,319 (AT2 receptor
antagonist), BQ123 (ETA receptor
antagonist), or IRL1038 (ETB
receptor antagonist) before stimulation with 30 mg/mL BSA
or 10-7 mol/L PMA for 30 minutes. The
presence of the Ang II and ET-1 receptor antagonists in the
incubation media significantly inhibited the NF-B activity caused by
BSA but not that induced by PMA
(Figure 5C), indicating that this effect is rather specific
and therefore not related to all NF-B activators.
Neither Ang II nor ET-1 receptor antagonists alone had any
significant effect on NF-B activation in our experimental
conditions. In addition, the stimulation of tubular epithelial cells
with Ang II (10-7 mol/L) and ET-1
(10-7 mol/L) increased NF-B activity in
a time-dependent manner, with the maximal NF-B activity after 30
minutes of stimulation
(Figure 6, A and C). The Ang II–induced NF-B activation
was inhibited with the preincubation of cells with losartan and
PD-123,319
(Figure 6B). The presence in the culture medium of BQ123 and
IRL1038 abrogated the ET-1–induced NF-B activation
(Figure 6D).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Progressive renal failure is characterized by proteinuria, inflammation, and scarring in the interstitium.1 Much evidence supports a role for proteinuria per se in the development of interstitial fibrosis,1 albeit the molecular mechanisms are still poorly understood. We first investigated whether in vivo protein overload could directly cause an increment in the renal NF-
B activity. This nonimmunological nephritis is
considered a valuable model to investigate the relation between
proteinuria and renal
damage.12 In relation to UNX
controls, BSA-overloaded rats showed an increment in renal NF-B
activity at all time periods studied that was well correlated with the
augmentation in the urinary protein excretion. By in situ Southwestern
histochemistry, NF-B was mainly localized in tubular epithelial
cells, interstitial cells, and, to a lesser extent, in the
glomeruli. However, tubular cells appear to be the major source of
NF-B because an increment in NF-B activation was found as early
as 24 hours after the administration of BSA, when no changes in the
number of renal infiltrating cells were observed. Also, in rats with
nephrosis induced by adriamycin, an increase in NF-B
activity was observed by day 7 (
4-fold), when there was only a mild
increment in the number of interstitial
cells.17 A correlation
between urinary protein excretion and renal NF-B activation
was also observed in rats with remnant kidney or rats with immune
complex
glomerulonephritis.16 18
Therefore, it could be speculated that intense proteinuria
increased NF-B activity in tubular epithelial cells and
upregulated many NF-B–dependent inflammatory genes. In fact,
increased expression of monocyte chemoattractant protein-1, RANTES, and
adhesion molecules was noted in experimental proteinuric renal diseases
(reviewed in Reference 11 ).
Because the mechanisms by which intense proteinuria could
induce NF-B activation and the expression of a number of genes are
not yet well understood, we approached the hypothesis that the
vasoactive peptides Ang II and ET-1 could be implicated in this
phenomenon. ACE inhibitors are considered the best therapy
available to date for proteinuric progressive
nephropathies.1 In this
regard, ACE inhibitors prevent proteinuria and NF-B
activation in some models of renal
injury.15 16 18
In this report, we demonstrate that the administration of quinapril
plus the ETA/ETB receptor antagonist bosentan during 28
days to UNX animals receiving 0.5 g BSA was associated with a
diminution in proteinuria, renal lesions, and NF-B activation more
markedly than each one individually. The mechanisms of the beneficial
effect when both drugs were given in combination were not defined in
this report. We can speculate that ACE inhibitors could
limit, at least partially, glomerular permeability to
proteins (as it is already known), whereas bosentan could prevent the
effect of enhanced ET-1 synthesis on
tubulointerstitial cells. In fact, the challenge of
cultured tubular epithelial cells with different proteins upregulates
ET-1 expression, which was mostly secreted toward in
interstitial
compartment.5 ET-1 stimulates
both interstitial fibroblast proliferation and
extracellular matrix synthesis and has potent chemotactic properties on
monocytes/macrophages.1 19
Thus, we have reported an increment in the production of ET-1
in proximal tubules of rats after 8 days of 1 g BSA
administration,3 4
coinciding with the increased NF-B activity in the renal cortex. In
addition, it has been demonstrated that the beneficial effects of ACE
inhibitors in the pathogenesis of renal damage could be a
result of decreased Ang II and ET-1
generation.20 21 22
In the same way, endothelin blockade prevents the
cardiovascular and renal effects of Ang
II.23 However, because
proteinuria, renal lesions, and NF-B activation were not fully
prevented by the combination of quinapril and bosentan, other
mechanisms may be implicated. In fact, numerous cytokines and
chemokines are produced by tubular cells when they are overloaded with
various
proteins.1 5 6 7
In rats with severe proteinuria and renal damage induced by
adriamycin, the administration of pyrrolidine dithiocarbamate
totally inhibited the cortical NF-B activation, although
interstitial monocyte/macrophage infiltration and
tubular injury were only partially
reduced.17 In this sense,
recent studies have shown that the simultaneous
administration of the immunosuppressor mycophenolate mofetil with an
ACE inhibitor or an AT1 receptor
antagonist to remnant kidney rats afforded better renal
protection than each single
drug.24 25
Preincubation of cultured tubular epithelial cells with Ang
II and ET-1 specific receptor antagonists inhibited the
BSA-induced NF-B activity. In addition, in these cells, Ang II and
ET-1 increased NF-B activity through AT1 and
AT2 receptors and ETA and
ETB receptors, respectively, as in the case of
BSA-induced NF-B activity. Although most of the known effects of Ang
II appear to be mediated by the activation of the
AT1 receptors, recent evidence suggests a
functional role for the AT2 receptor in the
kidney.2 26 In the
rat model of ureteral obstruction, both AT1 and
AT2 receptor antagonists decreased
NF-B activation in the obstructed kidney, though this effect was
greater with the AT1
antagonist.27
Furthermore, we have recently reported that the administration of the
AT1 antagonist losartan or
the AT2 antagonist PD123,319 to rats
receiving an infusion of Ang II (subcutaneously by osmotic minipumps)
inhibited the Ang II–induced NF-B activation, but only
losartan diminished AP-1
activation.28 In vitro, Ang
II caused the activation of NF-B through its
AT1 and AT2 receptors in
different cell
types.29 30 We
have recently reported that in vascular smooth muscle cells, both
receptors share some signaling pathways (oxygen radicals and ceramide).
However, tyrosine kinase only participates in NF-B activity induced
by AT1
activation.29
On the whole, our results demonstrate that protein overload
increases the activity of the transcription factor NF-B in tubular
epithelial cells both in vivo and in vitro. Together with previous
findings, the vasoactive peptides Ang II and ET-1 appear to be
implicated in the tubulointerstitial injury induced
by proteinuria. The present results reveal a novel mechanism of
perpetuation of renal damage induced by persistent
proteinuria.
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Acknowledgments |
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This work was supported in part by grants from Comunidad Autónoma de Madrid (08.4/0003/97; 08.4/0007.1/99), Fondo de Investigación Sanitaria (99/0425), Ministerio de Educación y Ciencia (PM 97/85), EU Concerted Action Grant BMH4-CT98-3631 (DG 12-SSMI), and Instituto de Investigaciones Nefrológicas "Reina Sofía." Dr Gómez-Garre, Dr Largo, and Dr Tejera are fellows from Comunidad Autónoma de Madrid, Ministerio de Educación y Ciencia, and Fundación Conchita Rábago, respectively.
Received January 5, 2000; first decision February 4, 2000; accepted September 22, 2000.
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