1 Department of Pediatrics, 3 Department of Molecular Biology and Pharmacology, and 2 Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, Missouri 63110
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ABSTRACT |
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C-type
natriuretic peptide (CNP) regulates salt excretion, vascular tone, and
fibroblast proliferation and activation. CNP inhibits fibroblast
activation in vitro and fibrosis in vivo, but endogenous CNP gene
(Nppc) expression during tissue fibrosis has not been
reported. We determined that Nppc is induced in renal tubular epithelia and then in interstitial myofibroblasts after unilateral ureteral obstruction (UUO). Induction of Nppc
occurred in identical cell populations to those in which
Wnt4 is induced after renal injury. In addition,
Nppc was activated in Wnt4-expressing cells
during nephrogenesis. Wnt signaling components -catenin and T cell
factor/lymphoid enhancer binding factor (TCF/LEF) specifically bound to
cognate elements in the Nppc proximal promoter. Wnt-4,
-catenin, and LEF-1 activated an Nppc transgene in
cultured cells, and transgene activation by Wnt-4 and LEF-1 was
dependent on the presence of intact cognate elements. These findings
suggest that Wnt-4 stimulates Nppc in a TCF/LEF-dependent
manner after renal injury and thus may contribute to limiting renal fibrosis.
myofibroblast; nephrogenesis; tubulointerstitial fibrosis; C-type natriuretic peptide
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INTRODUCTION |
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C-TYPE NATRIURETIC PEPTIDE (CNP) is one of a family of three related peptides that regulate fluid and electrolyte homeostasis (39). Expression of the CNP gene (Nppc) is detected at highest levels in the central nervous system, female reproductive tissues, and bone (7, 20). While CNP has vasodilatory action, circulating levels of CNP are low, and local autocrine and paracrine functions have been proposed (5). Mice with a targeted Nppc null mutation die during the neonatal period, with severe dwarfism due to a failure of endochondral ossification (7). One prominent role suggested for CNP is inhibition of myofibroblast function.
Myofibroblasts are cells that differentiate from fibroblasts after
tissue injury and proliferate and gain smooth muscle cell features such
as the expression of -smooth muscle actin. Myofibroblasts are
essential for wound matrix contraction and healing
(46) and secrete high levels of collagen, fibronectin, and
other extracellular matrix constituents. Myofibroblasts cease
proliferation and disappear during normal wound healing
(16) but can persist during chronic inflammation and
injury. CNP may be part of the mechanisms by which myofibroblast
activation is terminated. CNP inhibits hepatic myofibroblastic stellate
cell (45) and fibroblast (6) proliferation, and fibroblasts express the CNP receptor, natriuretic peptide receptor
B (NPR-B) (6). CNP administration prevents neointimal fibrosis and arterial smooth muscle cell proliferation following balloon angioplasty (15, 47). CNP inhibits basic
fibroblast growth factor-, platelet-derived growth factor-, and
epidermal growth factor-induced arterial smooth muscle cell
proliferation (36). Administration of CNP after renal
glomerular injury reduces glomerular fibrosis and limits the
proliferation of
-smooth muscle actin-positive mesangial cells
(4). These experiments demonstrate that exogenous CNP
administration inhibits the proliferation and activation of smooth
muscle cells and myofibroblasts and limits tissue fibrosis. However,
expression and regulation of CNP gene (Nppc) expression
after tissue injury have not been reported, and transcriptional
regulation of Nppc has not been extensively studied
(33). Here, we examined Nppc expression in a
well-characterized mouse model of renal tubulointerstitial fibrosis:
unilateral ureteral obstruction (UUO) (30).
Ligation of a single ureter results in extensive tubular cell damage, followed by macrophage influx and a fibrotic response (9, 10, 30). By 1 wk, smooth muscle actin-positive interstitial fibroblasts are apparent. One source of interstitial fibroblasts is transdifferentiation from tubular epithelial cells (23), which acquire expression of smooth muscle actin and other myofibroblast markers while still part of the tubular structure (31). Fibrosis continues to progress, with increasing epithelial loss, accumulation of interstitial myofibroblasts, and extracellular matrix deposition. By 4 wk after ligation, the entire kidney exhibits extensive fibrosis. We report that Nppc expression was induced after UUO, and in identical cell populations to those in which Wnt4 is induced.
The Wnt genes code for secreted glycoproteins that act
near their site of synthesis and are ligands for the frizzled
family of receptors (34, 51). Wnts regulate target gene
transcription through multiple intracellular signaling pathways
(29), with the best-studied pathway involving an increase
in the half-life of cytosolic -catenin (2, 53).
-Catenin regulates gene transcription by translocating to the
nucleus and interacting with transcription factors of the T cell
factor/lymphoid enhancer binding factor (TCF/LEF) family (2,
3). These factors are a subfamily of high-mobility group factors
that bind to specific DNA sequence elements (17, 50).
-Catenin contains no DNA binding domain but a transcriptional
activational domain. Wnt-4 is one member of the Wnt family that plays a
critical role in genitourinary development. Wnt4 is
activated in induced metanephric mesenchyme and is required for
metanephric mesenchymal condensation (43). Wnt-4 is
expressed in the developing Müllerian structures and is required
for female development (48). Wnt-4 is also expressed in
adult reproductive tissues including uterus (28), ovary
(19), and breast (14). We and others have
found that Wnt-4 is induced after renal injury leading to interstitial
fibrosis (32, 44). Wnt4 is first activated in
the collecting duct epithelium after UUO and then in the accumulating
interstitial myofibroblasts (44). We report our finding
that Nppc is induced in identical cell populations and at
the same time as Wnt4 in the injured kidney and test the hypothesis that Wnt signaling regulates Nppc expression.
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MATERIALS AND METHODS |
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Animals, ureteral obstruction, and tissue preparation. Approval was obtained from the Washington University Institutional Animal Care and Use Committee for all experiments involving animals. UUO was performed on anesthetized FVB/N and C57BL6/J mice of 6-7 wk of age and was accomplished by surgical cautery of the left renal ureter ~15 mm from the renal pelvis. The obstructed kidneys were harvested at 7 or 14 days after obstruction. Uninjured kidneys were harvested from 7-wk-old mice. Obstructed kidneys were frozen in OCT embedding medium for in situ hybridization. At least two obstructed kidneys were examined at each time point by in situ hybridization. Mouse embryos at day 17.5 of gestation (E17.5) were harvested after timed mating of 129SV/J mice.
RNA in situ hybridization.
Wnt4 and Nppc mRNA transcripts were detected in
murine samples by in situ hybridization of tissue sections. The
template used to produce murine Wnt4 riboprobes was a gift
from Andy McMahon (43). The in situ Wnt4
antisense riboprobe spans nucleotides 803 to 366 (GenBank NM009523).
The murine Nppc exon 2 was amplified by PCR from FVB/N mouse
genomic DNA. Primers used to generate the Nppc template were
5'-AGGTCCCGAGAACCCCG (sense) and 5'-ATGGAGCCGATCCGGTCC (antisense) to
generate a probe that complements nucleotides 1566-1721 (GenBank
D28873). The PCR products were ligated into the pZero 2.0 bacterial
plasmid (Invitrogen), and the sequence was verified. Radiolabeled
antisense riboprobes for in situ hybridization were transcribed using
linearized cDNA templates, [-33P]UTP (Amersham), and
the Promega in vitro transcription system. In situ hybridization was
performed utilizing 10- to 12-µm sections of OCT-embedded kidneys as
described (44).
Transient transfection assays and cell culture.
A transgene was constructed to include the Nppc sequence
spanning nucleotides 1209 to +56 relative to the start site of
transcription (GenBank U62939, nucleotides 6-1271). The fifty-six
transcribed nucleotides are outside the CNP open reading frame. The
Nppc promoter sequence was amplified by PCR from FVB/N mouse
genomic DNA, using primers 5'-TAATGGTACCCATGTCCATCCCAGCAGTCTTCC (sense)
and 5'-TGTGAAGCTTGGATTGCCAAGCGAGCACAG (antisense). The amplimer was
digested with KpnI and HindIII, and ligated into
pGL3 Basic vector (Promega) cut with the same enzymes. The resulting
plasmid contains the Nppc sequences
1209 to +56, including
the transcriptional start site, linked to firefly luciferase cDNA and a
transcriptional stop site. This transgene is termed
1209CNP.
Modifications in the Nppc promoter region of
1209CNP
detailed in Fig. 4A were introduced utilizing the Stratagene
QuickChange Site-Directed Mutagenesis Kit according to the
manufacturer's instructions. A murine Wnt-4 mammalian cell expression
plasmid was purchased from Upstate Biotechnology and contains the Wnt-4
open reading frame fused with the murine Wnt1 transcript
5'-untranslated sequences to increase Wnt-4 production (53). The expression plasmid for full-length
-catenin
plasmid in pCDNA3 was a gift from Stephen Byers (13). The
expression plasmid for full-length LEF-1 was a kind gift from Hans
Clevers. All transfections included plasmid pRL-TK (Promega) as a
control for transfection efficiency, and this plasmid expresses
Renilla luciferase from a viral promoter.
Gel mobility shift assays.
DNA for gel mobility shift assays (GMSAs) was produced by annealing two
complementary single-strand synthetic oligonucleotides to produce 15-bp
double-strand DNA (oligomers). An oligomer containing an optimal
TCF/LEF binding site: 5'-CCCTTTGATCTTACC (26) was radiolabeled with [-32P]ATP using polynucleotide
kinase (Roche). GMSAs were performed as described (41)
with the following exceptions: 25 ng of herring sperm DNA (Sigma) were
included in all reactions instead of poly(dI.dC), and 375 ng of bovine serum albumin and a 128-fold molar excess of competitor
oligonucleotide were included in each binding mixture. Three micrograms
of nuclear extract from SW480 cells were used per reaction. The SW480
nuclear protein extracts were prepared by ultracentrifugation
(11). GMSA supershift assays included 0.75 µg of
anti-
-catenin antibody (C19220, Transduction Laboratories) or 0.75 µg of anti-vimentin antibody (V6630, Sigma) in each binding mixture.
A 128-fold molar excess of various 15-bp oligomers was utilized
to compete with the radiolabeled optimal TCF/LEF binding site oligomer.
These competitor oligomers were derived from the core and flanking
sequences corresponding to each of the six potential Tcf/Lef sites in
the
1209CNP transgene (see Fig. 5A). Control competitions
were performed using a mutated optimal TCF/LEF binding site oligomer,
5'-CCCTTTGGCCTTACC (26), as well as
mutated oligomers corresponding to the modified Nppc Tcf/Lef
sites (see Fig. 5A).
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RESULTS |
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Nppc is induced during renal tubulointerstitial disease in cells
that express Wnt4.
Previous studies have defined an antifibrotic role for exogenous CNP
(15, 47), but Nppc expression during tissue
fibrosis has not been defined. Therefore, we examined the expression
pattern of Nppc during renal tubulointerstitial disease
progression after UUO. Nppc mRNA was not detected by in situ
hybridization in the uninjured kidneys of normal adult mice (Fig.
1A). One week after UUO,
strong Nppc expression was induced in the renal cortex (Fig. 1B). High-power views revealed that expression was confined
to collecting duct epithelial cells (Fig. 1,
C-E). This expression pattern is identical
to that of Wnt4 after UUO (44), where cortical expression in collecting duct epithelial cells was defined by the
presence of aquaporin-3 (44). In situ hybridization was performed to compare cellular localization of Wnt4 and
Nppc transcripts. One week after UUO, Wnt4 was
induced in the same collecting duct epithelial cells that support
Nppc expression (Fig. 1). Nppc may be active in a
greater number of the collecting duct epithelial cells than
Wnt4, perhaps reflecting paracrine action of this secreted protein. In the uninjured kidney, Wnt4 was detected only in
papillary collecting duct epithelial cells (Fig. 1F), in
contrast to Nppc, which was not detected. Wnt4 is
initially activated in the collecting duct epithelium and later in the
surrounding interstitial cells (44). Two weeks after UUO,
Wnt4 expression is evident in interstitial myofibroblasts
(44), and Nppc activation was observed in
identical cell populations (Fig. 2).
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Wnt4 and Nppc are expressed in the same cell populations during
renal development.
The precise temporal and spatial coincidence of Wnt4 and
Nppc induction after renal damage suggest the possibility
that both genes may be induced during renal development at the time
Wnt4 is activated. The expression pattern of Nppc
mRNA was determined in murine embryonic kidneys at 17.5 days of
gestation (E17.5) and compared with that of Wnt4.
Nephrogenesis is initiated when groups of metanephric mesenchymal cells
are induced by the ureteric bud to form condensates, which convert to
tubular epithelial structures and mature into nephrons. Nephrogenesis
in the developing kidney is an ongoing process, and the
E17.5 kidney contains nephrons at all stages of
nephrogenesis. Nppc mRNA (Fig. 3,
D-F) was
detected in the developing kidney in the nephrogenic zone.
Wnt4 is expressed in these same cells (Fig. 3,
A-C), as well as in the central stromal cells where Nppc is not expressed (Fig. 3, A vs.
D). Wnt4 expression is initially induced in the
condensing metanephric mesenchyme and remains active during metanephric
condensation and conversion of condensates to renal epithelial vesicles
and then comma- and S-shaped bodies. The earliest detectable
Nppc expression during nephrogenesis occurs in metanephric
mesenchymal condensates (Fig. 3F) in which Wnt4
is also expressed (Fig. 3C).
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Wnt-4 transactivates the Nppc promoter in cultured cells.
Wnt4 and Nppc are expressed in the same cells
after renal damage, suggesting that Wnt-4 may regulate Nppc
expression. Wnt-4 stabilizes cytosolic -catenin in cultured RatB1a
cells (44) and might activate Nppc through this
pathway in these cells. The RatB1a cells resemble the renal
myofibroblasts in which Wnt4 is activated in that they are
nontransformed fibroblasts that express high levels of
-smooth
muscle actin protein and collagen
1(I) mRNA (data not
shown). A transgene was constructed from murine Nppc
nucleotides
1209 to +56 relative to the start site of transcription linked to the firefly luciferase coding region as a reporter
(
1209CNP). Transient transfections were performed in the presence and
absence of a Wnt-4 expression construct to determine the effect
of Wnt-4 on Nppc activity (Fig.
4). Expression of Wnt-4 resulted in an increase in Nppc transgene activity.
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TCF/LEF family factors bind to sites in the Nppc promoter.
The possibility that Wnt-4 directly regulates Nppc
expression was explored. The canonical Wnt signaling pathway regulates gene transcription through binding of -catenin to TCF/LEF
transcription factors, which recognize specific binding sites in the
regulatory sequences of target genes. The start site of Nppc
transcription has been defined for the murine gene (20),
and we located six potential TCF/LEF binding sites in the 1,200 nucleotides 5' to the transcriptional start. These sites differed from
the consensus TCF/LEF binding sequence, 5'-CTTTGWW-3' (17, 49,
50), by one or two residues (Fig.
5A), although the core
sequence of site 1 is identical to that of a proven TCF/LEF
binding site in the c-jun regulatory region
(27). Thus Wnt-4 might directly activate Nppc
transcription through the localization of
-catenin bound to a
Tcf/Lef family member to the Nppc promoter.
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LEF-1 transactivates the Nppc promoter through interaction with
Tcf/Lef binding sites.
The functional significance of the six potential Nppc
Tcf/Lef binding sites was determined utilizing transient transfection assays in cultured cells. Transfections were performed in cultured RatB1a cells, which have properties of myofibroblasts, and also a rat
kidney tubular epithelial cell line, NRK52E (8). The renal
epithelial cell line and myofibroblast cell line were chosen for the
transfection assays because Wnt4 and Nppc
are initially activated in the renal epithelial cells (Fig. 1) and then
in interstitial myofibroblasts (Fig. 2). The ability of Wnt signaling
pathway components to transactivate the 1209CNP transgene was tested in the cultured cell lines. Both
-catenin and LEF-1 transactivated the
1209CNP transgene in both cell lines (Fig. 6, A and
B).
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DISCUSSION |
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We have identified Nppc as a gene regulated by Wnt-4,
LEF-1, and -catenin. The cell transfection assays and GMSAs
demonstrate that the Wnt-
-catenin-LEF-1 signaling pathway directly
stimulates Nppc through interaction with Tcf/Lef sites
1 and 2. Mutagenesis of Tcf/Lef sites 1 and
2 decreased but did not eliminate
1209CNP transactivation
by LEF-1, but no additional loss of transactivation occurred when all
six potential Tcf/Lef sites were mutagenized. These results are similar
to those reported for TCF/LEF/
-catenin regulation of
Axin2, where the promoter contains eight potential Tcf/Lef
sites and mutation of all sites together reduces but does not eliminate
-catenin activation of an Axin2 transgene
(24). TCF/LEF family members bind to DNA and achieve
transcriptional regulation of target genes through interaction with
coactivators such as
-catenin or corepressors such as groucho
homologues (2). We observed that LEF-1 alone achieves
significant activation of the Nppc transgene in both cell
lines, in agreement with previous studies showing that overexpression
of LEF-1 can mimic Wnt signaling (3, 38). The
Nppc Tcf/Lef element binds TCF4 and is activated by LEF-1,
but the identity of Tcf/Lef family members in the kidney and their
activity during injury and repair remain unknown. This pathway plays a
critical role in nephrogenesis, where Wnt-4 signaling is required, and
possibly in nephrogenic differentiation because PKD1 is a
target of Wnt
-catenin/TCF/LEF signaling.
We have linked the induction of Nppc expression to Wnt4 expression in renal development and after renal injury, in that Nppc is expressed in cells that also express Wnt4. Wnt4 is activated in the collecting duct epithelium and later in the surrounding interstitial cells (44) after renal damage, and Nppc was induced in identical cell populations and at the same time as Wnt4. These results are consistent with regulation of Nppc transcription by Wnt4, because Wnts bind tightly to the cell surface and are believed to act in an autocrine or paracrine fashion (34). Other Wnts are also present in the kidney and could potentially regulate Nppc expression through the same signaling pathway (32) in addition to or in conjunction with Wnt-4.
Nppc activation is not detected in the papillary epithelial cells that express Wnt4 in the normal kidney, implying that Wnt-4 is not sufficient for Nppc activation in the papillary collecting ducts. Other regulators present in the wounded kidney may be required in addition to Wnt4 to activate Nppc. It is also possible that inhibitors of Wnt signaling are active in the normal kidney to suppress Nppc activation. A role for CNP in wound healing is consistent with activation that is dependent on mediators present only during wounding. Renal damage initiated by numerous processes results in Wnt4 activation throughout the collecting ducts (44), suggesting a role for Wnt-4 in collecting duct function. Wnt-4 regulation of Nppc provides precedent for involvement of Wnt-4 in regulating other molecules that control electrolyte balance. It would be of interest to screen for Wnt-inducible genes in papillary collecting duct epithelial cells to detect other potential targets, because some of these may be active in the normal papillary collecting ducts. Wnt-4 may regulate genes in the normal kidney distinct from those it regulates in response to renal injury. Similarly, Wnt4 expression in the normal papillary collecting ducts may be regulated by a mechanism different from the one that activates Wnt4 expression in response to collecting duct injury. Alternatively, the most distal collecting ducts in the normal kidney may be subject to a greater degree of stress than the rest of the collecting ducts, and Wnt4 expression may be a response to recurring mild injuries in these cells.
Nppc induction after injury suggests the presence of a pathway for termination of wound healing and myofibroblast activation after injury. Extensive investigation has established that exogenous CNP inhibits myofibroblast proliferation and activation (6, 45), as well as prevents neointimal fibrosis after arterial injuries and glomerular fibrosis after renal injuries (4, 15, 47). Renal fibrosis induced by UUO does not resolve due to the sustained and continuing injury caused by permanent ureteral ligation, but Nppc induction may represent an attempt to control the ongoing fibrosis. Furthermore, CNP produced in the kidney may circulate and contribute to the vascular phenotype that accompanies chronic renal disease. CNP levels are increased in the plasma of diabetic rats (40) and humans with chronic renal failure (22). It would be of interest to test the requirement for Nppc in termination of myofibroblast activity after injury. This could be accomplished by comparing the extent of renal interstitial cell proliferation and amount of extracellular matrix accumulation after renal injury in normal mice to that in Nppc null mice rescued by CNP transgene expression in the bone (7). The potential of CNP to modify fibrotic progression could be determined by performing similar experiments in mice treated with exogenous CNP (4).
A wider role for CNP as a mediator of Wnt-4 action is suggested by
coincident expression of the two genes at other sites. Both
Wnt4 and Nppc are expressed in the growth plate
of bone. Proliferating chondrocytes normally exit the cell cycle during endochondral ossification to become prehypertrophic chondrocytes and
then hypertrophic chondrocytes. Misexpression of Wnt-4 in chick embryo
limb cartilage elements accelerates cell cycle exit of proliferating
chondrocytes, possibly through activation of the -catenin-LEF-1
signal transduction pathway (18). Nppc mRNA is
expressed in the proliferating chondrocytes and prehypertrophic chondrocytes (7). Nppc
/
mice
are defective in longitudinal bone growth due to a reduction in the
rate of maturation of proliferating chondrocytes to hypertrophic chondrocytes (7). These observations are consistent with
Wnt-4 regulating Nppc expression during chondrocyte
maturation. It will be of interest to determine whether the
misexpression of Wnt-4 in the chick cartilage elements results in
increased or premature Nppc expression in proliferating
chondrocytes. Wnt4 and Nppc are both expressed in
the endometrium, and levels of both are coincidently regulated
throughout the murine estrus cycle (1, 28, 37). It has
been suggested that CNP may mediate the tissue remodeling that occurs
in both wound healing and the estrus cycle (20). CNP might
also mediate similar remodeling during renal development, where
conversion of metanephric mesenchyme to epithelium is dependent on
Wnt-4.
CNP may inhibit cellular proliferation through elevated cGMP signaling. Binding of CNP to its receptor activates the NPR-B intracellular guanylyl cyclase domain, resulting in increased cytosolic cGMP. Increased cGMP activates intracellular signaling pathways that regulate cellular proliferation. Mice with a null mutation in the cGMP-dependent protein kinase II gene exhibit defective chondrocyte maturation (35), a finding consistent with the phenotype of the Nppc null mutation. In addition, CNP inhibits cultured hepatic myofibroblast cell proliferation through a mechanism dependent on protein kinase G activation by cGMP (45). CNP may also inhibit cellular proliferation through cGMP inhibition of the MAP kinase pathway to limit growth factor stimulation of cell proliferation (6, 45). Another mechanism by which CNP may inhibit cellular proliferation is through activation of the growth arrest-specific homeobox gene Gax and cyclin-dependent kinase inhibitor p21 (12, 52). CNP induces Gax expression in smooth muscle cells (52), and overexpression of Gax inhibits cell proliferation in a p21-dependent manner (42). Mice with a null mutation in the p21 gene have increased renal interstitial cell proliferation and higher numbers of interstitial myofibroblasts 3 days after UUO compared with that of wild-type mice (21). It is possible that Nppc activation after renal injury may limit renal interstitial cell proliferation and the extent of fibrosis through activation of p21.
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ACKNOWLEDGEMENTS |
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The authors thank Jan Kitajewski for the RatB1a cells, Katherine Lee and Lora Staloch for technical assistance, and David Wilson and John Majors for review of the manuscript.
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FOOTNOTES |
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This work was supported by the Pharmacia/Washington University Biomedical Research Program.
Address for reprint requests and other correspondence: T. C. Simon, Washington Univ. School of Medicine, Dept. of Pediatrics, Campus Box 8208, 660 S. Euclid Ave., St. Louis, MO 63110 (E-mail: simon_t{at}kids.wustl.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.
First published December 10, 2002;10.1152/ajprenal.00343.2002
Received 24 September 2002; accepted in final form 3 December 2002.
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