Department of Internal Medicine and Department of Integrative Biology and Pharmacology, The University of Texas Medical School at Houston, Houston, Texas 77030
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ABSTRACT |
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Transcriptional activation of the
inducible nitric oxide synthase (iNOS) gene requires multiple
interactions of cis elements and trans-acting
factors. Previous in vivo footprinting studies (Goldring CE, Reveneau
S, Algarte M, and Jeannin JF. Nucleic Acids Res 24:
1682-1687, 1996) of the murine iNOS gene demonstrated lipopolysaccharide-inducible protection of guanines in the region 904/
883, which includes an E-box motif. In this report, by using site-directed mutagenesis of the
893/
888 E-box and correlating functional assays of the mutated iNOS promoter with upstream
stimulatory factor (USF) DNA-binding activities, we demonstrate that
the
893/
888 E-box motif is functionally required for iNOS
regulation in murine mesangial cells and that USFs are in vivo
components of the iNOS transcriptional response complex. Mutation of
the E-box sequence augmented the iNOS response to interleukin-1
(IL-1
) in transiently transfected mesangial cells. Gel mobility
shift assays demonstrated that USFs cannot bind to the
893/
888
E-box promoter region when the E-box is mutated. Cotransfection of
USF-1 and USF-2 expression vectors with iNOS promoter-luciferase
reporter constructs suppressed IL-1
-simulated iNOS promoter
activity. Cotransfection of dominant-negative USF-2 mutants lacking the
DNA binding domain or cis-element decoys containing
concatamers of the
904/
883 region augmented IL-1
stimulation of
iNOS promoter activity. Gel mobility shift assays showed that only
USF-1 and USF-2 supershifted the USF protein-DNA complexes. These
results demonstrated that USF binding to the E-box at
893/
888
serves to trans-repress basal expression and IL-1
induction of the iNOS promoter.
transcription; glomerulus; inducible nitric oxide synthase; promoter; inflammatory cytokines; transcription factors; upstream stimulatory factor
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INTRODUCTION |
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NITRIC OXIDE (NO) is an important molecular mediator of numerous physiological processes in virtually every organ. NO is synthesized from L-arginine by the NO synthase (NOS) isozymes. Neuronal and endothelial NOS isozymes have restricted tissue distributions and are regulated in part by intracellular Ca2+ transients. Inducible NOS (iNOS) is expressed in a number of cell types in mammals after induction by cytokines and/or lipopolysaccharide (LPS) and, once expressed, is active at resting levels of intracellular Ca2+ (12). Induction of iNOS principally involves transcriptional activation, so considerable effort has been dedicated to identify the cis element and trans-acting factors that control its expression.
In the kidney, NO plays prominent roles in the homeostatic regulation of glomerular, vascular, and tubular function, as well as a variety of fundamental cellular functions, including DNA replication, transcription, energy metabolism, and apoptosis (12, 13, 17, 44). Although NO serves beneficial roles as a messenger and host defense molecule, excessive NO production can be cytotoxic, the result of NO's reaction with reactive oxygen species, leading to peroxynitrite anion, nitroxyl radical, and hydroxyl radical production and protein tyrosine nitration (2, 16). Recent studies provide clear evidence for participation of iNOS-generated NO in the induction, progression, or protection of several types of experimental and human glomerulonephritis. In human glomerulonephritis, iNOS gene expression has been described in glomerular mesangial cells, as well as in local and infiltrating macrophages (6, 41). Mesangial cells contribute prominently to the pathogenesis of glomerulonephritis, in part by producing a variety of cytokines and NO via iNOS. Consequently, the mesangial cell has been a center of investigational focus in this disease.
Structure-function analyses of the murine iNOS promoter/enhancer region
have identified several response elements that are functionally active.
LPS inducibility of the iNOS promoter activity in the mouse macrophage
cell line RAW 264.7 is largely dependent on a nuclear factor-B
(NF-
B)-binding element (
85/
76) (46) and an LPS
response element (45) in its proximal region. The synergistic effect of interferon (IFN)-
to activate iNOS promoter activity requires inclusion of distal promoter elements, including an
IFN regulatory factor-1-binding element (
923/
913)
(20), two sequential IFN-stimulated response elements, and
an IFN-
-activated site (7). The finding that LPS
induces footprinting of other regions of the murine iNOS promoter
suggested that other cis elements and
trans-acting factors contribute to iNOS induction. In
particular, we were intrigued by the observation from in vivo
footprinting of RAW 264.7 macrophage cells (8) that LPS
induces protection of guanines in the region
904/
883, which
contains a sequence
893 CATGTG 888 that conforms to an E-box element
(CANNTG), the suggested target site for DNA binding of basic
helix-loop-helix (bHLH) transcription factors. The identical sequence
is similarly positioned in the rat iNOS promoter.
The bHLH superfamily of transcription factors regulates growth and differentiation in a variety of tissues by forming transcriptionally active heterodimers that bind to E-box elements in the promoters of target genes. bHLH factors are important in developmental and tissue-specific expression of numerous genes but have not been classically attributed to regulation of proinflammatory genes (24). This class of transcription factors includes, among others, c-Myc (9), Max (9), E2A (11), sterol regulatory element-binding protein (34), and upstream stimulatory factors (USFs) (10). USF was originally identified as a factor that activates the adenovirus major late promoter (32). USF activity involves two polypeptides with apparent molecular masses of 43 and 44 kDa, which are referred to as USF-1 and USF-2, respectively (31, 33). The USF proteins form hetero- and homodimers (37) and bind to the E-box motif (37). USF proteins are thought to be involved in cell cycle regulation, including an antagonistic action against the function of c-Myc (3). In addition, USFs have been implicated in the control of several genes, including the genes for C/EBP (38), liver-type pyruvate kinase (39), type 1 collagen (27), and fatty acid synthase (40).
We have examined the functional importance of the 893/
888 E-box
element in the transcriptional competency of the murine iNOS promoter
in cultured mesangial cells. We provide evidence that this E-box is
required and USF-1 and USF-2 are in vivo components of iNOS regulation
by correlating functional assays and USF-binding activities to the
E-box. When the E-box was mutated, it was no longer a target for USF
binding, and the activity of the iNOS promoter was enhanced.
Cotransfection of USF-1 and USF-2 expression vectors with the iNOS
promoter suppressed iNOS promoter activity, and dominant-negative USFs
lacking the DNA binding activity augmented interleukin-1
(IL-1
)
induction of the iNOS promoter activity. Our results suggest that the
USF proteins play important roles in constraining iNOS induction in
mesangial cells and, thus, may serve to limit untoward effects of
excessive NO in the mesangium and glomerulus.
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EXPERIMENTAL PROCEDURES |
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Reagents.
Poly(dI-dC)-poly(dI-dC) was purchased from Pharmacia-LKB Biotech.
Oligonucleotides were custom synthesized by Genosys (The Woodlands,
TX). The Dual-Luciferase Reporter Assay System and the luciferase
vectors pGL3-basic and pRL-TK were obtained from Promega, the
bicinchoninic acid protein estimation kit from Pierce Chemical, RNAzol
reagent from TEL-TEST (Friendswood, TX), the endotoxin-free plasmid
Maxi-prep kit from Qiagen (Santa Clarita, CA), and mouse recombinant
IL-1 from Genzyme (Cambridge, MA). Rabbit polyclonal IgG antibodies
raised against bHLH proteins USF-1 (C-20) (21, 23), USF-2
(C-20) (21), c-Myc (sc-764) (42), E2A
(sc-416) (15), Id-1 (sc-427) (43), and BETA3
(sc-6045) were obtained from Santa Cruz Biotechnology (Santa Cruz, CA); these antibodies have been shown to recognize the corresponding mouse
proteins (see manufacturer's catalog and Refs.
28-32).
Cell culture.
Mouse mesangial cells (American Type Culture Collection) were cultured
at 37°C in complete medium (Ham's F-12 + DMEM supplemented with
2 mM L-glutamine, 100 U/ml penicillin, 100 µg/ml
streptomycin, and 5% FBS). Vehicle or IL-1 (10 ng/ml) was added to
the cells as indicated.
Plasmids and site-directed mutagenesis.
The iNOS promoter-luciferase construct piNOS-luc, which contains a DNA
fragment comprising nucleotides 1486 to +145 of the murine iNOS
promoter/enhancer in pGL3-basic, was used as the wild-type iNOS
promoter-luciferase construct. Deletion and site-directed mutation of
the
904/
883 segment in piNOS-luc was accomplished by PCR splicing
using overlap extension, with the wild-type iNOS promoter/enhancer cDNA
as template. For deletion of the
904/
883 element, forward primer P1
was used with mutagenic reverse primer P3
(5'-TCCAATAAAGCATTCAGCATGGAATTTTC-3') in the upstream reaction, and
mutagenic forward primer P4 (5'-AATGGAAAATTCCATGCTGAATGCTTTAT-3') and
reverse primer P2 were used in the downstream PCR. For mutation of the
893/
888 E-box (CATGTG replaced with
ACTGCT), the upstream reaction contained
forward primer P1 and mutagenic reverse primer P5
(5'-TCCAATAAAGCATTCAAGCAGTGCATGGAATTT-3'),
whereas mutagenic forward primer P6
(5'-AATGGAAAATTCCATGCACTGCTTGAATGCTTTA-3')
and reverse primer P2 were used in the downstream reaction. The
full-length site-deleted or -mutated iNOS promoter/enhancer was then
constructed in a PCR containing 50-fold dilutions of the upstream and
downstream PCR products from the initial PCR together with primers P1
and P2. The mutated P1-P2 promoter fragment PCR products were first cloned into pCR2.1, sequenced to verify the presence of the desired mutations and the absence of spurious mutations, and then subcloned into pGL3-basic to create the recombinant molecules piNOS-delE-box-luc (deleted E-box) and piNOS-
E-box-luc (mutated E-box).
Expression plasmids psv-USF1 and psv-USF2, as well as a
dominant-negative psv-USF2
B, were provided by Dr. Michele Sawadogo
(University of Texas M. D. Anderson Cancer Center). psv-USF2
B
encodes a USF-2 protein that lacks the DNA-binding domain but is able
to dimerize with USF-1 or USF-2 and, thereby, inhibits them in a
dominant-negative fashion (22).
Transient transfection and reporter gene assays.
Mesangial cells were seeded in six-well plates and grown to ~70%
confluence in DMEM + 10% FBS without antibiotics. On the following day, the cells were cotransfected with 4.5 µg/well of pGL3-basic, piNOS-luc, piNOS-delE-box-luc, or piNOS-E-box-luc, together with 0.5 µg/well of the Renilla luciferase
expression plasmid pRL-TK, using the LipoFectamine PLUS reagent
according to the manufacturer's protocol. At 24 h after
transfection, the medium was replaced with complete medium and vehicle
or IL-1
. After 16 h, cell lysates for measurement of firefly
and Renilla luciferase activities were prepared using
Passive Lysis Buffer (Promega) according to the manufacturer's
directions, and firefly and Renilla luciferase activities
were measured as described in our previous report (10a). For
trans-repression assays, pGL3-basic or piNOS-luc was
transfected with psv-USF1, psv-USF2, or psv-USF2
B, together with 0.5 µg/well of pRL-TK.
Electrophoretic mobility shift and supershift assays.
Nuclear extracts were prepared from mesangial cells, and
electrophoretic mobility shift assay (EMSA) was performed as previously described (14). Double-stranded oligomers for use as
probes or competitors (Table 1) were
generated by annealing complementary single-stranded oligonucleotides
and were 5'-end-labeled with [-32P]ATP (3,000 Ci/mmol)
using T4 polynucleotide kinase. Binding reactions (20 µl) containing
5-10 µg of nuclear extract protein, 1.75 pmol of duplex DNA
probe (~2 × 105 cpm), and reaction buffer [25 mM
HEPES, pH 8.0, 50 mM KCl, 0.1 mM EDTA, 1 mM MgCl2, 1 mM
dithiothreitol, 10% glycerol, and 50 µg/ml poly(dI-dC)-poly(dI-dC)]
were conducted for 30 min at room temperature. To demonstrate sequence
specificity of the protein-DNA interactions, binding reactions were
conducted in the presence of a 50-fold molar excess of nonradiolabeled
specific heterologous oligomers. For supershift assays, the
probe-nuclear protein complexes were allowed to form for 15 min at
25°C, and then antibodies (2 µg) specific for USF-1, USF-2, c-Myc,
E2A, Id-1, or BETA3 transcription factors or a comparable amount of
nonimmune IgG were added to the binding reaction and incubated at room
temperature for another 30 min. Aliquots of all reactions were
electrophoresed through 5% native polyacrylamide gels, and the dried
gels were subjected to autoradiography for detection of the shifted
bands.
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Ultraviolet cross-linking analysis.
Scaled-up EMSAs (100 µl reaction volume) were performed as described
above, but using 50 µg of nuclear extract and 106 cpm of
904 to
883 probe, which had been modified to contain bromodeoxyuridine and bromodeoxycytosine in place of dT and dC (Genosys) on both strands to increase ultraviolet (UV) cross-linking efficiency. After electrophoresis of the binding reaction,
autoradiograms of the wet gel were prepared to localize the shifted
complexes. The complexes were individually excised, and the gel slices
were UV irradiated (254 nm) in a Stratalinker (Stratagene) at
4°C for 1 h, boiled in Laemmli's sample buffer for 2 min, and
electrophoresed on SDS-10% polyacrylamide gels. The gels were dried
and autoradiographed to detect the constituent protein bands.
Northern analysis.
Total cellular RNA was extracted from cell monolayers using RNAzol II.
The samples were quantitated by spectrophotometry at 260 nm. For
Northern analysis, cDNA probes specific for the murine iNOS and
glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (14) were
labeled with 32P by the random primer method according to
the manufacturer's instructions (Prime-a-Gene, Promega, Madison, WI).
Fifteen micrograms of total RNA per lane were separated by size on 1%
agarose-2% formaldehyde gels and blotted to nylon membranes (Hybond N,
Amersham). After UV cross-linking, the blots were visualized under UV
light and prehybridized for 2 h at 68°C in QuickHyb solution
(Stratagene). The blots were sequentially hybridized with the murine
iNOS and GAPDH DNA probes, with the blots being stripped before the
next analysis, and washed to a final stringency of 0.1× saline-sodium citrate-0.1% (wt/vol) SDS at 60°C. Autoradiographs of the
blots were prepared at 70°C.
Cis-element decoy assays.
Double-stranded phosphorothioate oligonucleotides containing a
four-repeat palindrome of the wild-type 904/
883 sequence (sense
strand
904
5'-AATGGAAAATTCCATGCCATGTGTGAATGCTTTATT-3'
883)
or the
904/
883 sequence bearing a mutated E-box
(5'-AATGGAAAATTCCATGCACTGCTTGAATGCTTTA-3') were
generated by annealing complementary oligonucleotides in 1×
saline-sodium citrate at 95°C. Double-stranded oligonucleotides (150 nM) were transfected into mesangial cells as described above for
plasmid preparations. At 16 h after transfection, RNA was harvested from the cells for Northern analysis, or, in separate plates,
nuclear extracts were prepared for EMSA.
Data analysis. The intensities of bands on the Northern blot autoradiograms were measured by whole band densitometry software running on a SPARC Station IPC (Sun Microsystems, Mountain View, CA) equipped with an image analysis system (Bio Image, Ann Arbor, MI). Quantitative data are presented as means ± SE and were analyzed for significance by ANOVA. Significance was assigned at P < 0.05.
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RESULTS |
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Binding of nuclear proteins to the
904/
883 region of the iNOS
promoter.
To determine whether the
893/
888 E-box could bind nuclear proteins
from mesangial cells, EMSAs were performed using wild-type and
E-box-mutated oligomers derived from the murine iNOS promoter as probes
or competitors. Probe A (Table 1) contains the E-box element
as well as the neighboring guanine residues that were protected in
previous in vivo footprinting studies (8). EMSA using
nuclear extracts from vehicle-treated cells with probe A resulted in formation of a DNA-protein complex (Fig.
1A). IL-1
treatment
resulted in greater amounts of the complex. Sequence specificity of the
binding activity was verified in competition experiments with excess
unlabeled probe A or heterologous DNA (Fig. 1A).
Excess unlabeled probe A exhibited comparable
sequence-specific competition for the DNA-protein complexes from the
vehicle and the IL-1
-treated cells (Fig. 1A). To
determine the sequence boundaries important for formation of the
DNA-protein complexes, competition experiments were performed in EMSAs
with oligomer A as probe and 50-fold molar excesses of
unlabeled oligomer B, C, or D as competitors. These competitor oligomers represent partially overlapping segments of
oligomer A. The DNA-protein complex was partially competed by excess oligomer B or C (Fig. 1B),
both of which overlap the E-box. Oligomer D, which does not
overlap the E-box, did not competitively suppress binding. Furthermore,
no DNA-protein complex was formed in EMSAs using the mutated E-box
probe AEboxm (Fig. 1C). Mutation of the E-box in the probe abolished formation of the gel shift complex
in nuclear extracts prepared from vehicle- and IL-1
-treated cells
(Fig. 1C). Thus, although it is possible that other
trans-acting factors contribute to the DNA-protein complex
of the entire
904/
883 region, they do not contribute to the gel
shift complex specific for the E-box.
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893/
888 E-box sequence and
USF-1 and USF-2 suppress maximal IL-1
induction of the iNOS
promoter.
To determine whether the
893/
888 E-box represents an IL-1
response element within the iNOS promoter, the promoter activities of a
wild-type iNOS promoter-luciferase construct (piNOS-luc) and two
derived constructs in which the E-box was deleted (piNOS-delE-box-luc) or mutated (piNOS-
E-box-luc) were tested in transient transfection experiments of mesangial cells treated with vehicle or IL-1
(Fig. 4). As expected, piNOS-luc exhibited
negligible promoter activity under basal conditions but robust promoter
activity after IL-1
treatment of the cells. In contrast, the
IL-1
-induced promoter activity of piNOS-delE-box-luc or
piNOS-
E-box-luc was only ~60% of that of piNOS-luc. These results
suggest that the
893/
888 E-box functions to regulate negatively
IL-1
induction of iNOS gene transcription in these cells.
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DISCUSSION |
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In the course of glomerular injury, mesangial cells respond to
circulating cytokines or those produced by invading inflammatory cells
by increasing iNOS gene expression and NO production. Because of the
potential for excessive NO production to prove toxic to the host cells,
complex layers of regulatory control have been placed on the iNOS gene.
In this report, we showed that site-directed mutation of the
893/
888 E-box of the iNOS promoter abolished the USF binding to
this region in vitro and disrupted the IL-1
regulation of the
piNOS-luc reporter constructs in transfection assays of mesangial
cells. The supershift results indicate that the DNA-protein complexes
principally contain USF-1/USF-2 heterodimers. When cotransfected with
the iNOS promoter constructs, USF-1 and USF-2 inhibited and
dominant-negative USF-2 could further activate IL-1
-stimulated iNOS
promoter activity. In agreement with these findings, transfection of
cis-element decoy oligonucleotides of the
893/
888 E-box
enhanced IL-1
induction of the iNOS gene in these cells.
Interestingly, blockade of USF action by overexpression of a
dominant-negative USF-2 construct (Fig. 5) or transfection of the E-box
cis-element decoy (Fig. 6B) resulted in an
increase in basal iNOS promoter activity and mRNA abundance,
respectively, suggesting a constitutive role of USF-1 and USF-2 to
silence basal iNOS expression. Collectively, these data demonstrate
that USF binding to the E-box at
893/
888 suppresses iNOS
transcription and its induction and, thereby, may serve to constrain
excessive production of NO by this enzyme. Given the limited
transfection efficiencies of mesangial cells and the fact that only a
fraction of the cells are successfully transfected, these results may
underestimate the effects within the transfected cells. Because NO has
been shown to be antiproliferative in mesangial cells (4,
29), our findings suggest yet another mechanism by which USF may
regulate cellular proliferation.
USFs belong to the bHLH leucine zipper family of transcription factors characterized by a highly conserved COOH-terminal domain responsible for their dimerization and DNA binding. Structurally, USF-1 and USF-2 are highly related, except at the NH2 terminus (19). USF-1 and USF-2 are structurally related to the Myc family of proteins and normally bind to an E-box as dimers (homodimers as well as heterodimers) (37). Because of the demonstration of USF involvement in the transcriptional activation of the adenovirus major late promoter, USFs have been reported as potential regulators of numerous cellular genes involved in different important cellular processes. The effect on cell proliferation is in part related to the involvement of USF in regulation of p53 (26), cdc2 (5), and the cyclin B1 gene (5). USF is also involved in modulation of ras and c-myc transformation (1, 18).
Although the USF-1 and USF-2 genes are ubiquitously expressed in mammalian cells, the relative abundance of USF-1 and USF-2 gene product varies among cell types (36). It has recently been shown that the function of USFs is modulated in a cell-specific manner. This regulation depends on a short sequence stretch between the NH2-terminal transactivation domain and the DNA-binding domain known as the USF-specific region, which is critical for transactivation and nuclear localization (25). The cell specificity of USF proteins within the kidney is unknown, and there have been no reports of USF expression in glomerular mesangial cells. Given their ability to regulate a number of genes involved in cell proliferation and now iNOS, these proteins may prove to have important roles in modulating proliferative and inflammatory glomerular diseases.
The array of pathological conditions in which iNOS is maximally
expressed is derived from different signals inducing iNOS and the
involvement of different transcriptional activators to control its
transcription. Recent work suggests that combinatorial interactions
among transcription factors, and perhaps accessory proteins, may be
important for specificity in the responsiveness of the iNOS gene to
various stimuli in different cells types (30). USFs are
known to interact with other transcription factors to alter gene
transcription, (28, 35); whether USF-1 and USF-2 exert
their inhibitory effects on iNOS transcription by interfering with
other transactivators remains to be examined. In this regard, a number
of cis elements neighboring the 893/
888 E-box have been
shown to be functionally important in enhancing LPS- or
cytokine-mediated iNOS induction in other cell types, including
IFN-
-activated site elements at
942/
934 and
879/
871 and an
NF-
B element (
971/
962). However, the fact that iNOS mRNA was
expressed basally, without IL-1
induction, when USF binding to the
E-box element was blocked with cis-element decoys suggests
that at least the basal effect of USF to limit iNOS transcription does
not involve interference with inducible transcription factors, such as
NF-
B or STAT-1, known to transactivate the iNOS gene.
The rodent and human iNOS promoters differ substantially in sequence
and regulatory control. The proximal promoter of the human iNOS gene
contains two CATGTG E-box elements at 358/
353 and
1832/
1827.
However, the context of these elements with regard to neighboring
consensus binding elements differs from the functional E-box element in
the mouse iNOS promoter reported here. Thus it remains to be
established whether USF proteins exert regulatory control on human iNOS
transcription in a manner similar to that of the murine gene.
In the kidney, physiological amounts of NO have an important role in the regulation of renal hemodynamics, as well as sodium and water excretion (13). On the other hand, NO release as a result of cytokine-mediated activation of iNOS in mesangial cells can be sustained and lead to oxidative injury in various forms of glomerular inflammation. Accordingly, inhibition of iNOS expression and/or activity could be an effective anti-inflammatory strategy. Through their ability to suppress iNOS activation, USF-1 and USF-2 appear to serve this function in mesangial cells in vivo. However, given the large amounts of NO generated by maximally activated iNOS, the specific biological responses to a partial (~40% in the case of the USF protein reported here) inhibition of iNOS transcription are difficult to predict. In this regard, the ability of the USF proteins to suppress iNOS gene expression under basal conditions may serve as an important constitutive brake on the expression of the iNOS gene and the production of NO.
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ACKNOWLEDGEMENTS |
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We thank Dr. Q.-W. Xie (Cornell University) for helpful technical suggestions.
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FOOTNOTES |
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B. C. Kone was supported by National Institutes of Health Grants RO1 DK-50745 and P50 GM-20529. A. K. Gupta was supported by a National Kidney Foundation Research Fellowship.
Address for reprint requests and other correspondence: B. C. Kone, Dept. of Internal Medicine and Dept. of Integrative Biology and Pharmacology, The University of Texas Medical School at Houston, 6431 Fannin, MSB 4.148, Houston, TX 77030 (E-mail: Bruce.C.Kone{at}uth.tmc.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
May 22, 2002;10.1152/ajpcell.00100.2002
Received 5 March 2002; accepted in final form 22 May 2002.
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