1 Departments of Pathology and 2 Medicine, Northwestern University, Chicago, Illinois 60611; 3 Third Department of Internal Medicine, Okayama University, Okayama, Japan; and 4 Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, Texas 77550
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ABSTRACT |
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Renal-specific oxidoreductase (RSOR), an enzyme relevant to diabetic nephropathy, is exclusively expressed in renal tubules. Studies were initiated to determine whether, like other tubule-specific proteins, it selectively modulates tubulogenesis. Northern blot analyses revealed a ~1.5-kb transcript, and RSOR expression was detectable in mice embryonic kidneys at day 13, gradually increased by day 17, and extended into neo- and postnatal periods. RSOR mRNA and protein expression was confined to proximal tubules, commencing at gestational day 17 and increasing subsequently, but remained absent in glomeruli and medulla. Treatment with RSOR antisense oligodeoxynucleotide resulted in a dose-dependent dysmorphogenesis of metanephric explants harvested at gestational day 13. The explants were smaller and had expanded mesenchyme, and the population of tubules was markedly decreased. The glomeruli were unaffected, as assessed by mRNA expression of glomerular epithelial protein 1 and reactivity with wheat germ agglutinin. Antisense treatment led to a selective reduction of RSOR mRNA. Immunoprecipitation also indicated a selective translational blockade of RSOR. These findings suggest that RSOR is developmentally regulated, exhibits a distinct spatiotemporal distribution, and probably plays a role in tubulogenesis.
nephrogenesis; diabetes mellitus
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INTRODUCTION |
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FORMATION OF NEPHRONS COMMENCES with intercalation of the ureteric epithelial bud into the mesenchyme; as a result there is a phenotypic induction in which mesenchymal cells acquire the properties of epithelial cells (22, 24, 26). Subsequently, the nascent nephrons undergo a series of developmental stages, i.e., condensate, S-shaped body, precapillary, and capillary. The S-shaped body stage has been regarded as the precursor of two distinct processes, i.e., glomerulogenesis and tubulogenesis, which are related to the spatial segmentation of the S-shaped body. Relative to the anatomic location of the ureteric bud branches, the S-shaped body has a distal and proximal convolution or pole. The cells in the distal pole, i.e., those near the tips of ureteric bud branches, are believed to be the precursors of epithelium-lined tubular structures, whereas those in the proximal convolution develop into a renal glomerulus. The glomerulus during the latter part of the gestation (beginning on day 13 in mice) is capillarized by the process of vasculogenesis and angiogenesis (1), while the tubular epithelial cells undergo multiplication as well as differentiation (13). These developmental processes are regulated by a number of factors or macromolecules, i.e., extracellular matrix glycoproteins, their receptors, cell adhesion molecules, protooncogenes, tyrosine kinase receptors, growth factors, and transcription factors (15).
During this time, the tubular epithelia acquire polarity characteristics and reabsorptive transport properties (13, 26). The latter are believed to influence the handling of water, ions, amino acids, and sugars by the renal tubular epithelia (20). In the kidney, there are two types of glucose transporters: 1) facilitative glucose transporters, i.e., GLUT-1, -2, -4, and -5, and 2) sodium glucose cotransporters, i.e., SGLT-1 and -2. The latter are exclusively expressed in the tubules and have been shown to selectively modulate tubulogenesis (32). Similarly, other molecules that are exclusively expressed in the tubules, e.g., tubulointerstitial nephritis antigen, also selectively regulate tubulogenesis, while glomerulogenesis is unaffected (16). With the use of representational difference analysis of cDNA, an enzyme that is exclusively expressed in the kidney tubules has been identified recently in newborn mice (31). The enzyme has been termed renal-specific oxidoreductase (RSOR) and is relevant to glucose metabolism, and it begins to express in the tubules in the same time frame as SGLT-1 (32). In view of these properties of RSOR, studies were undertaken to assess its developmental regulation during metanephrogenesis in mice and to delineate its role in tubulogenesis vs. glomerulogenesis.
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MATERIALS AND METHODS |
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Animals. ICR mice (Harlan Sprague Dawley, Indianapolis, IN) were used for paired male and female mating, and appearance of the vaginal plug was designated day 0 of gestation. The mouse embryos were harvested at days 13, 17, and 19 (newborn) of gestation, and metanephroi were isolated. In addition, kidneys from 1-, 2-, and 3-wk-old mice were procured.
Gene expression of RSOR in developing kidneys by Northern blot
analyses and in situ hybridization tissue autoradiography.
RNA from embryonic kidneys at various stages of gestation and from
kidneys of 1- and 3-wk-old mice was extracted by the guanidinium isothiocyanate-CsCl centrifugation method (8). Equal
amounts of RNA were glyoxalated and subjected to 1% agarose gel
electrophoresis in 10 mM sodium phosphate buffer, pH 7.0. A Northern
blot was prepared by transferring the RNA to a nylon filter membrane
(Amersham, Arlington Heights, IL). The membrane blot was hybridized
with [-32P]dCTP-labeled mouse RSOR cDNA. The membrane
filter was washed under high-stringency conditions with 0.1×
saline-sodium citrate (SSC)-0.1% SDS at 60°C, and autoradiograms
were prepared. The same blot was also hybridized with a
-actin probe.
RSOR protein expression in developing kidneys by immunofluorescence microscopy. Kidneys of embryos at days 13 and 17 of gestation and of newborn and 1-, 2- and 3-wk-old mice were snap-frozen in chilled isopentane and embedded in OCT compound (Miles Laboratories, Elkhart, IN). Cryostat sections (4 µm thick) were prepared and air dried. Sections were washed with 0.01 M PBS, pH 7.4, and incubated with polyclonal anti-RSOR antibody (1:100 dilution) for 30 min in a humidified chamber at 37°C. After they were washed with PBS, sections were reincubated with goat anti-rabbit IgG antibody, conjugated with fluorescein isothiocyanate, for 30 min. The sections were rewashed with PBS, covered with a drop of buffered glycerol, mounted on coverslips, and examined with an ultraviolet microscope equipped with epi-illumination.
Antisense experiments. A sense-, a nonsense-, and an antisense-phosphorothioated oligodeoxynucleotide (ODN) were synthesized by an automated solid-phase synthesizer (Biotech Facility, Northwestern University) and purified by high-performance liquid chromatography. The antisense ODN sequence was selected from the 5' end of the RSOR as follows: 5'-GGATGCGCTTCCTGCTGACGAAGTCCACAGTCTGGTG-3'. The sequence of nonsense ODNs was as follows: 5'-TAATGATAGTAATGATAGTAATGATAGTAAT-3' and 5'-GATCGATCGATCGATCGATCGATCGATCGAT-3'. Neither ODN (antisense and nonsense) exhibited any significant homology with other mammalian nucleotide sequences available in the GenBank database, and their specificity was determined by S1 nuclease protection assay, as described in our previous publications (19, 30).
A total of ~750 embryonic kidneys at day 13 of gestation were harvested and maintained in culture for 1-4 days. The details of the metanephric culture have been described previously (19, 30). Briefly, the explants were placed on top of a 0.8-µm Nucleopore filter (Millipore, Bedford, MA) and transferred to a petri dish containing serum-free culture medium. The medium consisted of equal volumes of Dulbecco's modified Eagles' medium and Ham's nutrient mixture F-12, supplemented with iron-poor transferrin (50 µg/ml) and streptomycin and penicillin (100 µg/ml). The ODNs were added to the culture media daily at concentrations ranging from 0.5 to 1.5 µM for 1-4 days. At these concentrations, the ODNs usually retain their translational blockade specificity with no discernible cytotoxic effects (7, 19, 30). About 250 explants per variable, i.e., sense, antisense, and nonsense, were processed for light microscopy, quantitative RT-PCR analyses, and immunofluorescence and immunoprecipitation (IP) studies. Another ~300 untreated explants, serving as control, were also processed for various studies. For light microscopy, the Epon-embedded explants were sectioned at the midplane, such that the section included a maximum number of ureteric bud iterations, both poles, and the hilum of the embryonic kidney.Competitive RT-PCR analyses of antisense ODN-treated embryonic
kidneys.
Competitive RT-PCR analyses were carried out to assess the effect of
antisense ODNs on RSOR mRNA expression; the technical details of this
method have been described previously (19, 30). Briefly,
total RNA was isolated from 50 explants per variable by the acid
guanidinium isothiocyanate-phenol-chloroform extraction method
(9). Extracted RNAs were treated with RNase-free DNase (Boehringer Mannheim, Indianapolis, IN) and then precipitated with
ethanol. About 50 µg of total RNA, from each variable, were subjected
to first-strand cDNA synthesis using Maloney's murine leukemia
virus-RT and oligo(dT) as a primer. The cDNAs from different variables
were suspended in 50 µl of autoclaved water and kept at 70°C.
Expression of de novo synthesized RSOR in antisense ODN-treated
renal explants.
IP studies were performed on renal explants treated with various ODNs,
i.e., antisense, sense, and nonsense, to assess the translational
blockade of RSOR. Treated explants were maintained in the organ culture
system and labeled with [35S]methionine (0.25 mCi/ml) for
12 h before the termination of culture. They were rinsed with the
culture medium. They were then extracted with 2 ml of IP buffer (50 mM
Tris · HCl, pH 7.5, 50 mM NaCl, 0.02% NaN3, 0.25 mM dithiothreitol, 1% Triton X-100, 10 mM -amino-
-caproic acid,
10 mM benzamidine HCl, 5 mM N-ethylmaleimide, and 1 mM
phenylmethylsulfonyl fluoride) by vigorous shaking for 4 h at
4°C. The extract was microfuged, and the supernatant was saved. Total
incorporated radioactivity was determined in the supernatant after
trichloroacetic acid precipitation. Samples with equal amounts of
radioactivity (~5 × 106 dpm) in a volume of 500 µl were used for IP, as previously described (19, 30).
Polyclonal rabbit anti-RSOR antibody (10 µl) was added and gently
swirled at 4°C in an orbital shaker for 12 h at 4°C. The
antigen-antibody complexes were briefly microfuged and transferred to a
fresh Eppendorf tube. After addition of 10 mg of protein A-Sepharose 4B
(Pharmacia LKB Biotechnology, Piscataway, NJ), in a volume of 100 µl
of the IP buffer, the complexes were further incubated for 1 h at
4°C. They were then centrifuged for 1 min at 10,000 g, and
the pellets were washed extensively with the IP buffer. Pellets
containing the complexes were suspended in 20 µl of sample buffer
(4% SDS, 150 mM Tris · HCl, pH 6.8, 20% glycerol, 0.125%
bromphenol blue, 1 µl of
-mercaptoethanol, and 1 mM
phenylmethylsulfonyl fluoride). Aliquots of the samples were boiled and
subjected to 10% SDS-PAGE. The gels were fixed in 10% acetic acid and
10% methanol, treated with 1 M salicylic acid, and vacuum dried, and
autoradiograms were prepared.
Tissue expression of RSOR, wheat germ agglutinin, and GLEPP-1 in antisense-treated metanephric explants. Tissue expression of RSOR in tubules of antisense and sense or nonsense ODN renal embryonic explants was assessed by immunofluorescence microscopy as described above. To evaluate the concentration of nascent glomeruli in the antisense ODN-treated explants, expression of wheat germ agglutinin (WGA) and GLEPP-1 was assessed, since both are regarded as markers for the podocyte and the latter is a highly differentiated cell of the renal glomerulus. The adjacent serial sections were stained with anti-RSOR and WGA conjugated with rhodamine (Sigma Chemical, St. Louis, MO) at a dilution of 1:100 and photographed as described above. The cryostat sections from the midplane of the explant included a maximum number of ureteric bud iterations, and tubules and glomeruli were examined. Finally, the mRNA expression of GLEPP-1 was determined in the RSOR antisense-treated explant by in situ tissue autoradiography. The 467-bp product generated above by PCR was used to prepare the GLEPP-1 riboprobe. Conditions for hybridization of the GLEPP-1 riboprobe and preparation of the autoradiograms were essentially as described for the RSOR.
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RESULTS |
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RSOR mRNA expression by Northern blot analyses.
A single ~1.5-kb mRNA transcript in kidneys harvested from embryos at
days 13 and 17 of gestation and newborn and 1- and 3-wk-old mice was observed (Fig.
1A). The mRNA expression of
RSOR was detectable at day 13 of gestation when ~25 µg
of total RNA, isolated from ~100 explants, were used. The RSOR mRNA
expression steadily increased during the various stages of
gestation and was notably accentuated during neo- and postnatal stages,
suggesting that it is developmentally regulated. No other transcript
was seen throughout development, indicating that no other related
isoform, e.g., aldose reductase or aldehyde reductase, is expressed
during embryonic development. The mRNA expression of -actin was
constant throughout the embryonic, neonatal, and postnatal periods in
mouse kidneys (Fig. 1B).
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Expression of RSOR by tissue in situ autoradiography and
immunofluorescence microscopy.
Because RSOR is developmentally regulated, in situ hybridization and
immunofluorescence studies were performed to examine its spatiotemporal
distribution in embryonic and neonatal kidneys (Fig.
2). At day 13 of gestation,
the expression was not distinct, and a very mild reactivity was
observed in the ureteric bud branches in some of the metanephric
explants (Fig. 2, A and G). At day 17,
expression of RSOR was seen in the cortical tubules in the form of
clusters, and the message was absent in the medulla (Fig. 2,
B and H). In the newborn, the pattern of mRNA
expression was similar to that at day 17, although it was
accentuated (Fig. 2, C and I). The mRNA
expression was further accentuated and became diffuse among the
cortical tubules in the kidneys of 1-wk-old mice (Fig. 2, D
and J). However, it remained absent in the medulla. Also no
message was detected in the renal glomeruli (arrowheads in Fig.
2J). In the kidneys of 2-wk-old (Fig. 2, E and
K) and 3-wk-old (Fig. 2, F and L)
mice, RSOR was highly expressed in the cortical tubules and was absent
in other compartments of the kidney.
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Role of RSOR in tubulogenesis of the mammalian metanephros
(antisense experiments).
Metanephric explants treated with ODNs at 0.5, 1.0, and 1.5 µM were
examined. The embryonic renal explants treated with nonsense or sense
ODNs at 1.5 µM did not reveal any significant morphological change
compared with the untreated metanephroi (Fig.
4, B and F, vs.
Fig. 4, A and E). The ureteric bud branches
exhibited normal iterations, and the glomeruli and tubules were well
developed. There were fewer glomeruli than tubules after 4 days of
culture. Usually, at this stage of culture, the population of the
tubules is four to seven times that of the glomeruli. The explants
treated with antisense ODN exhibited notable alterations. There was an overall dose-dependent reduction in the size of the explants. ODN at
0.5 µM in the medium (Fig. 4, C and G) reduced the nephron population and expanded the mesenchyme. The reduction of nephrons was
mainly confined to the tubules, although a very mild decrease in the
glomeruli was observed as well. The mesenchyme in the deeper portion of
the explant was loose. Antisense ODN at 1.0 µM further reduced the
size of explants (not shown). Antisense ODN at 1.5 µM remarkably
reduced the number of tubules, and very few tubules were seen (Fig. 4,
D and H). The glomerular population seemed to be
unaffected, and a number of them were readily discernible (arrowheads
in Fig. 4H). They seemed to be aggregated perhaps because of
the loss of tubules. The ureteric bud branches were rudimentary, and
their normal dichotomous iterations were not seen. The mesenchyme
seemed to be enormously expanded.
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RSOR and GLEPP-1 mRNA and protein expression studies (antisense
experiments).
To assess the transcriptional and translational RSOR-specific blocking
activities of antisense ODN, competitive PCR, IP, and in situ
hybridization studies were performed. Competitive RT-PCR was chosen to
circumvent the difficulties related to minute amounts of mRNA available
for Northern blot analyses from embryonic explants harvested at
day 13 of gestation. Within the range of
101-10
8 serial logarithmic dilutions
of the competitive (mutant) template DNA dilution, the bands of
wild-type and mutant DNA were discernible (Fig.
6, A-C, lanes 1-8),
enabling densitometric analyses to obtain a ratio of the intensities of
the bands. The graphic plots have been published previously (19,
30), and only the original data, i.e., electrophoretograms, are
included to indicate the intensity of the bands. In the nonsense
ODN-treated (control) explants, a ratio of 1 for the reductase mRNA was
obtained at dilutions of 10
3-10
4 of
the competitive (mutant) DNA (Fig. 6, A, lanes 3 and
4). In the antisense ODN-treated explants, a ratio of 1 for
reductase mRNA was obtained at dilutions of
10
5-10
6 of the competitive DNA (Fig.
6, A, lanes 5 and 6), suggesting a decrease on
the order of 2 logs of the mRNA expression in the antisense ODN-treated
explants. For
-actin and GLEPP-1, a ratio of 1 was obtained at
dilutions of 10
3-10
4 in the antisense
ODN-treated groups, which is similar to their corresponding controls
(Fig. 6, B and C, lanes 3 and 4),
suggesting no decrease in their mRNA expression.
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DISCUSSION |
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RSOR belongs to a family of aldoketoreductases (AKRs), which are monomeric oxidoreductases with molecular weight ranging from 35 to 40 kDa and include >60 members (2, 14). They are expressed in a wide variety of tissues, where they catalyze the NADPH-dependent reduction of various aliphatic and aromatic aldehydes and ketones. The exact substrate for RSOR (GenBank accession no. AF197127) is unknown, but tentatively it is classified as aldehyde reductase-6. Although various members of the AKR are expressed in the kidney, in addition to other organ systems, the information that relates to their developmental expression is limited. RSOR-related enzymes, i.e., aldehyde reductase (AKR1A) and aldose reductase (AKR1B), have been isolated and characterized from the placenta (10, 29). Because the placenta has a dual origin, i.e., chorion frondosum from the fetus and decidua basalis from the mother, it is likely that these enzymes may be expressed in fetal tissues as well. In this regard, the mRNA expression of AKR1B has been studied in human fetal tissues, although no information is available in the literature as to the spatiotemporal expression of AKR1A during embryonic development. AKR1B is mildly expressed in certain fetal tissues, including fetal brain, lung, liver, eye, and kidney (6). Beyond AKR1B expression in fetal tissues, no further functional studies have been performed. However, further detailed studies describing spatiotemporal expression of AKR1B have been described in the rat eye (3), and interest in this area may be due to its relevance in one of the common complications of diabetes, i.e., cataractogenesis. At day 13 of murine gestation, there is a relatively high degree of mRNA expression in the optic cup compared with other organs. The level of expression continues to be high in subsequent stages but is confined to the germinative zone, the latter being the source of cells that become lens fibers. Because of such a spatiotemporal expression, AKR1B has been implicated in lens fiber morphogenesis (3). In the rat kidney, AKR1B mRNA expression is mostly detectable at a very late stage of gestation and is mainly seen in medullary tips of the newborn kidney. Its expression rises rapidly and, by postnatal day 12, reaches levels comparable to those in the adult kidney (4, 25). Because AKR1B expression in the kidney is a late occurrence, it probably has a lesser role in the renal morphogenesis.
RSOR is exclusively expressed in the fetal kidney and exhibits strict spatiotemporal distribution. The mRNA expression is detectable at day 13 of mouse gestation. Thereafter, it steadily increases during the later stages of gestation and reaches levels comparable with those in the adult kidney by 3 wk of postnatal life (Fig. 1). Because RSOR expression is detectable just after the commencement of nephrogenesis, it is conceivable that it may have a role in metanephrogenesis similar to other macromolecules that are expressed at that stage of embryonic development (5, 26). Some of the molecules that are known to regulate nephrogenesis are exclusively expressed in the tubules, and they selectively modulate tubulogenesis (16, 32). Because RSOR is exclusively expressed in the tubules at the onset of nephrogenesis and is confined to the proximal tubules (Figs. 2 and 3), it would be of interest to investigate whether it affects tubulogenesis and/or glomerulogenesis. So far, the molecules that have been described to exclusively modulate tubulogenesis include extracellular matrix proteins, i.e., tubulointerstitial nephritis antigen and an integral membrane protein, SGLT-1 (16, 32). Here, a relevant issue therefore would be whether a cytosolic protein such as RSOR can modulate tubular development. Also, because it is difficult to assume that a given molecule is relevant to nephrogenesis or tubulogenesis simply because it is developmentally regulated, one has to prove this by performing in vitro or in vivo gene disruption experiments.
To address these issues, in vitro antisense ODN experiments were performed. This technology has yielded critical information in various developmental processes, provided appropriate controls are included in a given experiment (5). In cell culture systems, a high dose of various antisense ODNs (>10 µM) can be used, whereas in an organ culture system such as that of the kidney, this dose is quite toxic; i.e., one may observe foci of necrosis or apoptosis in antisense-treated explants. In view of this fact, the experiments were performed at 0.5-1.5 µM, which yielded dose-dependent alterations in the metanephric explants, and no discernible toxicity was observed (Fig. 4). The alterations in the metanephroi included expansion of the mesenchyme and a notable loss of tubules, while the population of glomeruli was unaffected. This loss of tubules and intact population of glomeruli could be confirmed by various glomerular markers, including WGA staining (Fig. 5) and GLEPP-1 in situ tissue hybridization (Fig. 6). Although these findings may suggest that antisense ODNs selectively affect tubulogenesis, the important question would be whether these effects specifically target RSOR. The fact that competitive RT-PCR revealed a 10- to 100-fold decrease in the mRNA expression of RSOR would suggest that the antisense ODN effects specifically target the RSOR gene (Fig. 6). Further support for these findings is derived from the translational blockade studies, in which a marked decrease in the intensity of the ~33-kDa band, corresponding to the protein size of RSOR, was observed in explants treated with antisense ODN, while the band of explants treated with nonsense ODN was unaffected. Thus a comparable decrease in mRNA and protein expression would suggest that the antisense ODN effects are specifically targeted at the RSOR, which resulted in a decrease in the population of tubules. Also, largely intact glomerulogenesis would support the fact that the effects specifically target the tubules. The deficiency of tubules in the antisense-treated explants may be related to the failure in their differentiation and maturation from the nephron progenitor elements. Also, it may in part be due to the atrophy or regression of the tubules that have previously matured and are present at day 13 of gestation in mice metanephric explants. The selective deficiency of tubules in the treated explants may be due to the ready uptake of the antisense ODNs by the tubular cells compared with that by the glomeruli. However, this may be unlikely, since the nonsense-treated glomeruli did not show much discernible change, and moreover, the alterations observed with antisense treatment were dose dependent.
Interestingly, the effects described above are reminiscent of the previously reported results for SGLT-1, which exhibits similar spatiotemporal expression in the kidney during embryonic life (32, 33). Because these two macromolecules have similar spatiotemporal expression and both are involved in glucose energy metabolism, it is conceivable that the glycolytic pathway plays a critical role in tubular maturation compared with its relevance in glomerular development. This is more of a speculation at present, and further studies on the expression of these molecules during development in kidneys exposed to high glucose concentrations are required. In this regard, it is known that high glucose ambience can induce dysmorphogenesis of the embryonic kidney in in vitro culture systems (17). Also, it is worth mentioning that hyperglycemia, besides causing diabetic nephropathy (18, 21), is also known to cause renal developmental abnormalities in 2-3% of offspring of poorly controlled juvenile diabetics, which may be part of the "caudal regression syndrome" or may solely involve the urogenital system (11).
In summary, the results of this investigation suggest that RSOR, an enzyme involved in glucose metabolism, is developmentally regulated and modulates renal tubulogenesis in an in vitro organ culture system. Finally, it is anticipated that the results of this investigation would provide an impetus for future in vivo genetic manipulation studies, i.e., transgenic and knockout mice experiments, to elucidate the role of RSOR in renal development under normoglycemic and hyperglycemic states.
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ACKNOWLEDGEMENTS |
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This study was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-28492, DK-36118, and DK-60635 and Japanese Ministry of Education Grants 10770199 and 11470218. S. Chugh is the recipient of National Institute of Diabetes and Digestive and Kidney Diseases Clinician Scientist Development Award DK-61275.
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FOOTNOTES |
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Address for reprint requests and other correspondence: Y. S. Kanwar, Dept. of Pathology, Northwestern Univ. Medical School, 303 East Chicago Ave., Chicago, IL 60611 (E-mail: y-kanwar{at}northwestern.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.
10.1152/ajprenal.00181.2001
Received 8 June 2001; accepted in final form 19 October 2001.
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