Vol. 280, Issue 1, F88-F94, January 2001
Cytochrome P-450 as a source of catalytic iron
in minimal change nephrotic syndrome in rats
Hua
Liu1,
Sudhir
V.
Shah2, and
Radhakrishna
Baliga1
1 Department of Pediatrics, University of Mississippi
Medical Center, Jackson, Mississippi 39216; and 2 Department
of Medicine, University of Arkansas for Medical Sciences, Little
Rock, Arkansas 72205
 |
ABSTRACT |
We have recently
demonstrated an important pathogenic role for glomerular catalytic iron
in the puromycin aminonucleoside (PAN) induced minimal change nephrotic
syndrome (MCNS). The source of this iron capable of catalyzing free
radical reactions is not known. We examined the role of cytochrome
P-450 (CYP) as a source of catalytic iron in a model MCNS
induced by single injection of PAN to rats. Treatment of PAN resulted
in a marked increase in the catalytic iron associated with significant
loss of glomerular CYP content. Administration of CYP inhibitors
significantly prevented the injury-induced loss of CYP content and the
increase in the catalytic iron in the glomeruli accompanied by a marked
decrease in proteinuria. In an in vitro study utilizing glomerular
epithelial cells (GEC), CYP inhibitors also markedly prevented the
PAN-induced increase in the catalytic iron and hydroxyl radical
formation accompanied by significant protection against PAN-induced
cytotoxicity. Taken together our data indicate that the CYP, a group of
heme protein, may serve as a significant source of this catalytic iron.
reactive oxygen metabolites; puromycin aminonucleoside; glomerular
epithelial cells; cytochrome P-450 inhibitors
| |
INTRODUCTION |
MINIMAL CHANGE
NEPHROTIC SYNDROME (MCNS) IS THE MOST COMMON NEPHROTIC syndrome
that affects children between 2 to 6 years of age. Reactive oxygen
metabolites (ROM) are important mediators of this renal injury
(5, 31). The molecular mechanism for the generation of ROM
is not clear. Hence, the treatment of the MCNS is empirical, requiring
mostly corticosteroids and at times immunosuppressive agents. A better
understanding of the mechanism of this glomerular injury may lead to
therapy with fewer complications.
Iron, a transition metal, plays an important role in in vivo and in
vitro models of reactive oxygen metabolites-mediated tissue injury
(4-7, 17, 31). The ease with which iron is reversibly oxidized and reduced, while essential for its metabolic functions, also
makes iron potentially hazardous because of its ability to participate
in the generation of powerful oxidant species, hydroxyl radical (the
metal catalyzed Haber-Weiss reaction) and/or in the generation of the
highly reactive iron oxygen complexes such as ferryl or perferryl ion
(17). In vivo most of the iron is bound to heme and
non-heme proteins and does not freely catalyze the generation of
hydroxyl radicals or similar oxidants (17). Gutteridge et
al. (14-17) have described an assay based on the use
of the antibiotic bleomycin to detect iron complexes capable of
catalyzing free radicals in biological fluids. By using this assay we
have reported a marked increase in the bleomycin-detectable iron in several models of acute renal failure (4, 6, 7) including puromycin aminonucleoside (PAN)-induced MCNS (33).
The source of this iron capable of catalyzing free radical reactions is
currently not known. Iron storage protein ferritin, transferrin,
iron-rich mitochondria, and under certain circumstances, extracellular
heme protein such as hemoglobin and myoglobin have all been suggested
as possible sources for this iron (25, 27). Recent
studies, including that of ours, indicate that the iron rich enzyme,
cytochrome P-450 (CYP), may serve as a potential source of
iron in models of tissue injury (8, 10, 26). However, the
role of CYP in any glomerular disease model including PAN-induced MCNS
has not been previously examined. Hence, the current study was designed
to examine the role of CYP, especially as a source of catalytic iron,
in an in vivo model of MCNS induced by a single injection of PAN to
rats and in an in vitro model of PAN-induced cytotoxicity to glomerular
epithelial cells (GEC).
| |
METHODS |
In vivo studies
PAN-induced nephrotic syndrome.
Male Sprague-Dawley rats weighing 200-250 g were injected with
saline or a single intravenous injection of PAN (Sigma, St. Louis) in a
dose of 7.5 mg/100 g body wt. (BW; day 0) as in our previous
study (33). Animals were housed in separate metabolic cages and allowed free access to rat chow (Purina). Daily urine protein
excretion was determined and animals were killed on day 7.
Blood was obtained for the measurement of serum albumin and the
evaluation of renal function as measured by blood urea nitrogen (BUN)
and plasma creatinine. Cell fraction of the glomeruli was prepared for
bleomycin-detectable iron assay. The microsome fraction was utilized
for the measurement of CYP content.
Inhibition of cytochrome P-450.
Two different inhibitors of CYP were used. Cimetidine (CM) has
imidazole and cyano groups that inhibit CYP by interacting with the
heme moiety (29). This effect of CM is specific for CYP,
as it does not interact with other heme enzymes (2). To determine the effect of the CYP inhibitors in PAN-induced nephrotic syndrome, CM (120 mg/kg BW) was administered intraperitoneal 1h prior
to PAN injection and then twice a day. Another CYP inhibitor, piperonyl
butoxide (PB), which yields a metabolite that binds to the heme moiety
of CYP (1, 12), was given intraperitoneal (400 mg/kg BW)
4 h before PAN injection and then every other day. All
experimental procedures were conducted in accordance with our
institutional guidelines.
Isolation of glomeruli.
Glomeruli were isolated by a combination of sieving and differential
centrifugation as in our previous studies (3, 33). Glomeruli isolated from two rats were pooled together (as
n = 1) for the isolation of microsomes.
Bleomycin-detectable iron assay.
Iron capable of catalyzing free radical reactions was measured by
bleomycin-detectable iron assay as described by Gutteridge et al.
(15, 16) and as detailed in previous studies from our laboratory (6-8, 33).
Cytochrome P-450 content in microsome.
Glomeruli isolated from rat kidneys were suspended in an extraction
buffer containing 20 mM Tris · HCl, pH 7.4, 0.25 M sucrose, 1 mM EDTA and protease inhibitor cocktail (5 µl/100 mg wet weight, Sigma, St. Louis, MO) and frozen at 
80°C. Subsequently, the
glomeruli were thawed and sonicated (22). The homogenate
was centrifuged at 15,000 g for 20 min at 4°C and the
precipitate was discarded. The microsomes were sedimented by
centrifugation of the supernatant at 105,000 g for 60 min at
4°C. The firmly packed pellet of microsomes was resuspended in above
extracting buffer at a concentration of ~10 mg protein/ml
(32). CYP content was measured by the method of Omura and
Sato (24). In brief, suspension of microsome from the
glomeruli was diluted to about 1 mg of protein/ml with the assay buffer
(0.1 M potassium phosphate buffer, pH 7.25, 20% glycerol, and 0.2%
tergitol). After the baseline was recorded, the sample was reduced with
a few crystals of dithionite, and followed by CO bubbling for ~1 min.
The CO difference spectrum of reduced microsomes was recorded on a
Shimadzu UV-2101PC spectrophotometer. The peak absorbance at 450 nm was
measured, and the amount of CYP was determined by using the extinction
coefficient of 91 mM/cm.
In vitro studies
Cell culture.
Rat GEC (kindly provided by Dr. Saulo Klahr, Washington University
School of Medicine, St. Louis, MO) were maintained in RPMI-1640 medium
supplemented with 10% fetal bovine serum, 15 mM HEPES, insulin,
penicillin, streptomycin, and L-glutamine in a humidified atmosphere of 95% air-5% CO2 at 37°C and fed at
intervals of 3 days (20). The cells were maintained in
75-cm2 tissue culture flasks and the monolayers were
subcultured by using 0.05% trypsin-0.53 mM EDTA in Hank's balanced
salt solution (HBSS). For the experimental study, the cells were grown
in 12-well tissue culture plate until confluence.
PAN-induced cytotoxicity.
On the day of experiment, the medium was discarded and the
confluent GEC monolayer was washed twice with HBSS. The cells were then
incubated with various concentrations of PAN (0, 0.1, 0.5, 1.0, 1.5, and 2.0 mM in HBSS) for different periods of time (0, 6 h, 1, 2, 3, and 4 days) at 37°C. At the end of the incubation, the incubation
medium was discarded and the GEC monolayer was harvested by
trypsinization with 0.05% trypsin-0.53 mM EDTA for 5 min at 37°C.
Isolated cells were suspended in HBSS to give ~106
cells/ml. Cell viability was determined by use of trypan blue exclusion
assay as in our previous study (9).
Effect of CYP inhibitors on the PAN-induced
cytotoxicity.
Confluent GEC monolayers were washed twice with HBSS and then incubated
with various concentrations of CM, ranitidine [(RN), as a control for
CM] for 30 min, and PB for 60 min at 37°C. After the
incubation, the cell monolayers were washed twice with HBSS and then
incubated with cytotoxic dose of PAN in HBSS for a period of time
necessary to induce consistent cytotoxicity (1.5 mM/ml, 48 h,
based on the concentration and time course studies) at 37°C.
PAN-induced cytotoxicity on GEC was measured by trypan blue exclusion assay.
Effect of CYP inhibitors on
PAN-induced catalytic iron release.
Confluent cell monolayer was washed three times with Chelex-treated
HBSS to remove as much contaminating iron as possible. The GEC
monolayer was then incubated in Chelex-treated HBSS with a cytotoxic
dose of PAN for a period of time at 37°C before
substantial cell killing and after significant iron release occurs (1.5 mM, 60 min, on the basis of a time course study on iron release induced
by PAN, data not shown). The incubation medium was then collected for
the measurement of catalytic iron by using bleomycin-detectable iron
assay as mentioned above. To determine the effect of CYP inhibitors on
the iron release, GEC monolayer was preincubated with CM (2 mM), RN (1 mM, as a control for CM) for 30 min or PB (25 µM) for 60 min in
Chelex-treated HBSS at 37°C. After the incubation, the medium with
CYP inhibitor was discarded and then the cell monolayers were washed
twice with chelex-treated HBSS prior to the incubation of PAN.
Effect of CYP inhibitors on
PAN-induced hydroxyl radical formation.
Confluent GEC monolayer was washed twice with HBSS and then incubated
with 1.5 mM PAN in HBSS for a period of time before substantial cell
killing occurs (1 h) at 37°C.
2-Deoxy-D-ribose in a final concentration of 3 mM was added to the medium just prior to the incubation. At the end of the incubation, the incubation medium was collected for the measurement of
hydroxyl radical formation by deoxyribose degradation method as in our
previous study (9). To determine the effect of CYP inhibitors on the hydroxyl radical formation, GEC monolayers were preincubated with CM, RN, or PB as mentioned above.
Statistical analysis.
Values are expressed as means ± SE. Statistical analysis was
performed by using unpaired t-test (for only two groups) and analysis of variance (for more than two groups). Statistical
significance was considered at P < 0.05.
| |
RESULTS |
Intravenous administration of PAN resulted in nephrotic range
proteinuria by day 7 (Fig.
1A). The catalytic iron
content as measured by the bleomycin-detectable iron assay was
significantly elevated from a control value of 39 to 160 nmol/mg
protein (n = 3, P < 0.01) in the
glomeruli obtained from rats injected with PAN (Fig. 1B). If
CYP serves as a source of this catalytic iron, there would be a marked
reduction in the CYP content in the glomeruli in the PAN-treated rats.
Indeed the CYP content in the PAN-treated rats was not detectable in
the glomeruli (Fig. 2). This loss of CYP
content in the glomeruli was injury specific because there was no
difference in the level of CYP content in the liver between the
untreated and the PAN-treated animals (Fig. 2).
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Fig. 1.
Puromycin aminonucleoside (PAN)-induced proteinuria
(A) and bleomycin-detectable iron content in the glomeruli
(B). PAN model of minimal change nephrotic syndrome in rats
was induced by single intravenous injection of PAN (7.5 mg/100 g BW).
The animals were killed 7 days after PAN injection. Values are
means ± SE. *P < 0.01 comparing PAN-treated rats
with control animals.
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Fig. 2.
Cytochrome P-450 (CYP) content in kidney (A)
and liver (B) in PAN-induced nephrotic syndrome in rats.
Values are means ± SE. N/D, not detectable.
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We postulated that the heme moiety of CYP may serve as a significant
source of iron in this model of injury. Hence, we examined the effect
of CYP inhibitors CM and PB (which interact with the heme moiety of
CYP) on the bleomycin-detectable iron content in the glomeruli in
PAN-treated rats. Both CM and PB significantly prevented the increase
in this iron in the glomeruli in rats subjected to PAN injection (Fig.
3). If the heme moiety of CYP serves as a
significant source of this catalytic iron then one would anticipate that the CYP inhibitors that prevent the increase in
bleomycin-detectable iron will also preserve the loss of CYP in the
glomeruli. We therefore measured the effect of these inhibitors on CYP
content in PAN-treated animals. Both CM and PB significantly preserved
the loss of CYP content in the glomeruli in the rats subjected to PAN
injection (Fig. 4). We next examined the
effect of these inhibitors on PAN-induced proteinuria. Administration
of PAN resulted in significant proteinuria on the fourth day with
marked increase thereafter throughout the course of the study (Fig.
5). Both CM and PB provided substantial protection against PAN-induced proteinuria (Fig. 5).
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Fig. 3.
Effect of CYP inhibitors on the bleomycin-detectable iron
content in the glomeruli of PAN-treated rats. Values are means ± SE. *P < 0.05 compared with control rats.
+P < 0.05 compared with PAN treatment
alone.
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Fig. 4.
Effect of CYP inhibitors on CYP content in the glomeruli
of PAN-treated rats. Values are means ± SE. N/D, not
detectable.
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Fig. 5.
Effect of CYP inhibitors on the proteinuria in rats
treated with PAN. Values are means ± SE. **P < 0.05 compared with the rats treated with PAN alone. +PB, piperonyl
butoxide; +CM, citmetidine.
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PAN-treated rats had significant weight gain at the time of death
compared with the control animals and those treated with CYP inhibitors
CM and PB (Table 1). The serum
albumin in the PAN-treated animals was markedly decreased and this
decrease was prevented by the CYP inhibitors CM and PB (Fig.
6). Renal function as measured by serum
creatinine was similar in all the groups while the BUN was slightly but
significantly elevated in the rats treated with PAN and CYP inhibitors
compared with the control animals (Fig.
7).
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Fig. 6.
Effect of CYP inhibitors on the serum albumin in rats
treated with PAN. Values are means ± SE. *P < 0.05 compared with the control rats.
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Fig. 7.
Renal function as measured by serum creatinine
(A) and blood urea nitrogen (BUN) (B) in rats
injected with PAN with or without CYP inhibitors. Values are means ± SE. *P < 0.05 compared with the control rats.
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We also examined the role of CYP in an in vitro model of PAN-induced
cytotoxicity to GEC. Exposure of GEC to PAN (1.5 mM) resulted in a
significant increase in the bleomycin-detectable iron content (Fig.
8). Both the CYP inhibitors, CM (2 mM)
and PB (25 µM), markedly prevented the increase in the
bleomycin-detectable iron content (Fig. 8). RN (1 mM), which has a
similar structure as CM but is a weak inhibitor of CYP, did not prevent
the marked increase in the bleomycin-detectable iron content (Fig. 8).
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Fig. 8.
Effect of CYP inhibitors on the catalytic iron release
from glomerular epithelial cells (GEC) exposed to PAN. Confluent GEC
was incubated with cytotoxic dose of PAN (1.5 mM) for a period of time
before substantial cell killing occurs (1 h). CYP inhibitors PB (25 µM), CM (2 mM) and ranitidine (RN) (1 mM, as a control for CM) were
preincubated with GEC for 30-60 min and then washed with chelexed
Hank's balanced salt solution (HBSS) followed by addition of PAN.
Values are means ± SE. *P < 0.05 compared with
the control; +P < 0.05 compared with GEC
exposed to PAN alone.
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Iron has been shown to participate in the generation of powerful
oxidant species, such as the hydroxyl radical via the metal catalyzed
Haber-Weiss reaction (5). We hence examined the potential role of hydroxyl radical in PAN-induced cytotoxicity to GEC. As shown
in Fig. 9, exposure of GEC to PAN led to
a significant increase in the hydroxyl radical formation. CYP
inhibitors CM and PB, but not RN, markedly reduced the PAN-induced
hydroxyl radical formation in the GEC.
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Fig. 9.
Effect of CYP inhibitors on the hydroxyl radical
generation in GEC exposed to PAN. Confluent GEC were incubated with
cytotoxic dose of PAN (1.5 mM) for a period of time before substantial
cell killing occurs (1 h). CYP inhibitors PB (25 µM), CM (2 mM), and
RN (1 mM, as a control for CM) were preincubated with GEC for
30-60 min and then washed with HBSS followed by addition of PAN.
Values are means ± SE. *P < 0.05 compared with
the control; +P < 0.05 compared with PAN
alone.
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PAN was cytotoxic to the GEC in a time and a dose-dependent manner as
measured by the trypan blue exclusion assay (Fig.
10). Both CM and PB but not RN
significantly reduced PAN-induced cytotoxicity to the GEC (Fig.
11).
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Fig. 10.
Concentration and time-dependent cytotoxicity of PAN in
GEC. Left: concentration-dependent effect of PAN (0 to 2 mM
for 48 h) and (right) time-dependent effect of PAN (0 h
to 4 days at PAN dose of 1.5 mM) on cytotoxicity in GEC as measured by
trypan blue exclusion assay. Values are means ± SE.
(n = 2).
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Fig. 11.
Effect of CYP inhibitors on the cell death in GEC
exposed to PAN. Confluent GEC was incubated with cytotoxic dose of PAN
(1.5 mM) for a period of time necessary to induce consistent
cytotoxicity (48 h). CYP inhibitors PB (25 µM; A), CM (2 mM; B), and RN (1 mM, as a control for CM; C)
were preincubated with GEC for 30-60 min and then washed with HBSS
followed by addition of PAN. Values are means ± SE.
*P < 0.05 compared with GEC exposed to PAN alone at
concentration indicated in the figure. (n = 3).
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| |
DISCUSSION |
The role of CYP in any model of glomerular disease has never been
examined. Our study indicates an important role of CYP in PAN-induced
MCNS. A single intravenous injection of PAN to rats results in marked
proteinuria and renal morphological changes similar to MCNS in humans
(23). We have demonstrated, in our previous study, a
significant increase in catalytic iron (as measured by
bleomycin-detectable iron assay) in the glomeruli in PAN-treated rats,
and the iron chelator deferoxamine markedly reduced the increase in the
catalytic iron associated with significant protection against
proteinuria (33). Our present data suggest that the major
role of CYP in this model of MCNS is to serve as a significant source
of catalytic iron.
Administration of PAN resulted in a significant increase in the
catalytic iron accompanied by loss of CYP content in the glomeruli. This loss of CYP content was specific to the glomeruli as there was no
difference noted in the levels of CYP content in the liver between PAN
and control group of animals. If the heme moiety of CYP does serve as a
significant source of this iron in PAN-induced MCNS, then the CYP
inhibitors that interact with the heme moiety of CYP should prevent the
increase in the bleomycin-detectable iron and preserve the loss of CYP
in this model. We used two different inhibitors of CYP to increase the
specificity of our observation. Both CM and PB prevented the increase
of the bleomycin-detectable iron in the glomeruli and the PAN-induced
loss of CYP content. They also provided significant protection against
PAN-induced proteinuria and the marked decrease in the serum albumin.
We also conducted an in vitro study by using GEC, which is the specific site of injury in MCNS. Exposure of GEC to PAN resulted in a
significant increase in the bleomycin-detectable iron content that was
prevented by both CYP inhibitors CM and PB. Because we have shown the
relationship between the loss of CYP content and the increase in
catalytic iron after administration of PAN in rats, we did not repeat
this study in vitro. Preincubation of the cells with CM and PB also provided significant reduction of PAN-induced cytotoxicity. RN, which
has three times the H2 receptor blocking activity as CM but
is a weak inhibitor of CYP, did not exhibit any protection.
One of the important mechanisms by which iron mediates tissue injury is
the generation of hydroxyl radical via the iron catalyzed Haber-Weiss
reaction (5, 17). The protective effects of iron chelators
and hydroxyl radical scavengers have been generally taken as evidence
for the participation of hydroxyl radical in PAN-induced MCNS
(5). We demonstrated that exposure of GEC to PAN resulted
in a significant increase in the hydroxyl radical formation. CYP
inhibitors, both CM and PB but not RN, significantly reduced the
PAN-induced hydroxyl radical formation. We have observed in our
previous studies that CYP inhibitors CM and PB do not chelate the
catalytic iron and scavenge hydroxyl radical in a cell-free system
(9). Hence, we speculate that the protective effect of CYP
inhibitors is due to their binding with CYP hemeprotein that protects
the heme moiety from oxidative injury and consequently prevents release
of catalytic iron. Taken together, these data indicate an important
role of CYP and support the notion that CYP serves as a critical
endogenous source of iron, capable of catalyzing free radical reactions
in PAN-induced MCNS. Our study however, does not exclude the other
roles of CYP in this model of renal injury. CYP participates in the
bioactivation and detoxification of a wide variety of substances. The
administration of CYP inhibitors may also influence such functions of
CYP that are relevant to the expression of renal injury by mechanism(s)
independent of iron.
The mechanism(s) responsible for the loss of CYP is not well defined.
In our previous studies, we have shown that the incubation of the
microsomes isolated from LLC-PK1 (renal proximal tubular cells) with hydrogen peroxide resulted in a marked increase in iron
mobilization. In addition, CYP inhibitor CM (but not RN) significantly
reduced the iron mobilization from the microsome fraction exposed to
hydrogen peroxide (9). Recent studies have demonstrated
enhanced generation of hydrogen peroxide from kidney slice cultures and
GEC exposed to PAN (21, 30). It is likely that such an
increase in the generation of hydrogen peroxide could result in direct
oxidative attack on the heme moiety of CYP, promoting the heme
destruction and the release of iron (19).
Our data does not exclude other intracellular sources of iron from
participating in ROM-mediated glomerular injury. For instance, mitochondrial cytochromes, iron-sulfur protein, and other iron containing proteins may be an alternative source of iron. Shah et al.
found that isolated renal cortical mitochondria released iron when
exposed to the nephrotoxic gentamicin (34). Zager and
coworkers suggested that the formation of
iron/H2O2-based reactive intermediates in
mitochondria may be responsible for the cell damage in an in vitro
model of myoglobin cytotoxicity (35). However, our study
indicates a close relationship between the catalytic iron formation and
the content of microsomal CYP, which is mainly involved in the drug
metabolism (18). In addition, CYP inhibitors were markedly
effective in reducing PAN-induced proteinuria in rats as well as
PAN-induced cytotoxicity to GEC. Thus we suggest that microsomal CYP is
the major source of the catalytic iron.
MCNS accounts for >75% of cases of nephrotic syndrome in children and
30% of nephrotic syndrome in adults (11, 13, 28). Treatment of minimal change disease is empirical because the underlying mechanism(s) that cause glomerular injury are not well known. Corticosteroids and/or immunosuppressive agents are often used to treat
minimal change disease (11, 13, 28). Our results indicate
that CYP inhibitors have a beneficial effect on proteinuria and may
have future clinical application not only in patients with MCNS but
also in other models of nephrotic syndrome as well.
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ACKNOWLEDGEMENTS |
This work was supported by a project grant from Kidney Care
Foundation (KCF-98029) awarded to R. Baliga.
| |
FOOTNOTES |
Address for reprint requests and other correspondence: R. Baliga, Dept. of Pediatrics, Division of Nephrology, Univ. of
Mississippi Medical Center, 2500 North State St., Jackson, MS
39216-4505 (E-mail: rbaliga{at}ped.umsmed.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.
Received 11 July 2000; accepted in final form 20 September 2000.
| |
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INTRODUCTION
