1 Department of Medicine, Shiga University of Medical Science, Shiga 520-2192; and 2 Discovery Research Laboratory, Tanabe Seiyaku Company, Limited, Osaka, Japan
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ABSTRACT |
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Persistent proteinuria has been indicated
to be a major risk factor for the development of tubulointerstitial
damage through a process of proinflammatory molecule expression.
Monocyte chemoattractant protein-1 (MCP-1) was shown to contribute to
recruitment of immune cells into the renal interstitium in acute and
chronic renal diseases. However, the molecular mechanisms by which
proteinuria causes MCP-1 expression in proximal tubular cells have not
been fully clarified. In this study, we examined whether albumin
overload-induced MCP-1 expression was regulated by mitogen-activated
protein kinase (MAPK) in mouse proximal tubular (mProx) cells. Exposure
of mProx cells to delipidated bovine serum albumin (BSA) induced mRNA
and protein expression of MCP-1 in a time- and dose-dependent manner. BSA activated extracellular signal-regulated kinase (ERK1/2) and p38
MAPK. The MEK inhibitor U-0126 partially suppressed BSA-induced MCP-1
expression and MCP-1 promoter/luciferase reporter activity. U-0126 also
inhibited an increase in nuclear factor-B and activator protein-1
DNA-binding activity of MCP-1 promoter by protein overload in mProx
cells. In addition, we found that U-0126 inhibited BSA-induced nuclear
factor-
B reporter activity and inhibitory protein degradation in
mProx cells. In conclusion, these findings indicate that ERK signaling
is involved in BSA-induced MCP-1 expression in mProx cells.
nuclear factor-B; tubulointerstitial damage
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INTRODUCTION |
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THE IMPORTANT CORRELATION between the degree of proteinuria and the risk of progression of renal disease has been recognized (5, 18). It is widely observed that patients with significant proteinuria are more likely to develop end-stage renal failure than those without proteinuria (21, 23, 25). It is also recognized that the degree of renal dysfunction correlates with histological abnormalities in the renal tubulointerstitium, rather than in glomeruli, even in primary glomerular disorders (4, 23, 27). These observations suggest that the severity of proteinuria is a major determinant of tubulointerstitial injury (21).
Recent reports have revealed that albumin, the major protein found in proteinuria, is able to induce phenotypic changes in proximal tubular cells and alter their function in a manner that produces proinflammatory chemokines in the renal tubulointerstitium (10). When proximal tubular cells are incubated with albumin, they produce monocyte chemoattractant protein-1 (MCP-1) and RANTES (regulated upon activation, normal T cell expressed and secreted) (31, 34). MCP-1 is an important chemoattractant for macrophages and T lymphocytes (2, 6, 16), which are the predominant inflammatory cells found in the interstitium in chronic glomerular disease (7, 17). Increasing evidence also suggests that MCP-1 may have an important role not only in the regulation of interstitial inflammation but also in other processes related to matrix deposition (17).
The intracellular mechanisms by which albumin upregulates MCP-1 in
proximal tubular cells have not been fully characterized. The promoter
region of the mouse MCP-1/JE gene contains putative binding sites for a
number of transcription factors, including the ubiquitous nuclear
factor-B (NF-
B)/Rel family and activator protein-1 (AP-1)
(20). NF-
B proteins normally exist in the cytosol as
dimers bound to inhibitory proteins (I
B). After exposure to diverse
stimuli, I
B undergoes proteolysis, allowing NF-
B to enter the
nucleus and activate the expression of genes encoding chemokines and
other proteins (1, 13). The significance of NF-
B in
regulation of the MCP-1 gene has been reported in various types of
cells, including renal cells (19, 26, 30, 32). For
instance, exposure of rat proximal tubular cells to albumin induced
NF-
B activation (32, 34). Inhibition of NF-
B with pharmacological agents (N-tosyl-phenylalanine chloromethyl
ketone and dexamethasone) or an antisense oligonucleotide to the rat p65 subunit of NF-
B significantly reduced albumin-induced MCP-1 transcription in rat proximal tubular cells (32).
On the other hand, recent evidence suggests that activation of AP-1 is
also required for induction of MCP-1. Shyy et al. (28) reported that AP-1 binding to
12-O-tetradecanoylphorbol-13-acetate-responsive elements is
critical for shear stress-induced expression of the MCP-1 gene. It has
also been reported that lipopolysaccharide, transforming growth
factor-, or interleukin-1
stimulates MCP-1 gene expression by
activating AP-1 in certain types of cells (19, 29, 33). A
role in the regulation of murine MCP-1/JE expression for the AP-1 site
exposed to tumor necrosis factor-
and transforming growth factor-
has been suggested by other studies, because MCP-1/JE expression was
decreased when antisense DNAs targeting c-Jun and c-Fos or inhibitors
of c-Jun and c-Fos were used (12, 29). AP-1 activity is
regulated by the mitogen-activated protein kinase (MAPK) superfamily.
At least three members of MAPK, extracellular signal-regulated kinase
(ERK), p38 MAPK, and the c-Jun NH2-terminal kinase (JNK)
have been identified to be involved in a wide range of cellular
responses to extracellular signals (24). Recently, Dixon
and Brunskill (9) demonstrated that albumin was able to
stimulate proliferation of proximal tubular cells via ERK, suggesting a
possible link between albuminuria and the derangements of proximal
tubular cell growth observed in progressive renal scarring. However, it
remains to be clarified whether ERK is involved in the regulation of
MCP-1 expression.
In the present study, we investigated the role of ERK activated by BSA in regulation of MCP-1 expression.
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METHODS |
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Materials
BSA (fatty acid free, fraction V) was obtained from Bayel (Pittsburgh, PA). BSA did not contain a high level of endotoxin (<3.0 ng/ml), as detected by the Endospacy method (SRL, Tokyo, Japan).Antiphospho-p42/p44 ERK, antiphospho-p38 MAPK, antiphospho-IB-
,
and anti-I
B-
antibodies were purchased from New England Biolabs
(Beverly, MA). Antiphospho-JNK antibody, U-0126, SB-203580, and
luciferase kit were purchased from Promega (Madison, WI). Anti-ERK2,
-p38 MAPK, and -JNK2 antibodies were obtained from Santa Cruz
Biotechnology (Santa Cruz, CA). Anti-
-actin antibody was obtained
from Sigma Chemical (St. Louis, MO). The 5×NF-
B luciferase reporter
vector (NF-
B-Luc) was obtained from Clontech (Palo Alto, CA).
[
-32P]dCTP and [
-32P]ATP were
purchased from New England Nuclear (Boston, MA). All other reagents
were of chemical grade and were purchased from standard suppliers.
Proximal Tubular Cell Culture
Microdissection of the proximal tubule. Proximal tubular segments were microdissected from C57BL/6J adult mouse kidney. The kidneys were perfused through the renal artery and excised, and coronal sections were cut with a surgical blade. The sections were transferred to a flask containing 10 ml of ice-cold Hanks' balanced salt solution containing 0.1% BSA and 0.1% type I collagenase, which was used to perfuse the kidneys. The flask was incubated for 10 min at 37°C in a shaking water bath. The samples were suffused with 5% CO2-95% O2 during the incubations. Tissues were transferred to Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum (FBS) and placed on ice. Then the proximal tubular segments were microdissected under a stereoscopic microscope.
Immortalization of proximal tubular cells. The microdissected proximal tubules were aspirated into 20 µl of K1 medium composed of 1:1 DMEM-Ham's F-12 culture medium with 10% FCS and placed on type IV collagen-precoated 96-well plates. The proximal tubules were maintained in a minimum volume of the modified 1:1 mesenchymal cultured K1 medium-fresh K1 medium for 24-48 h. After attachment to the culture plate, proximal tubules were cocultured with the mouse mesenchymal feeder cells. At ~7-10 days after microdissection, primary cell outgrowths were transfected with 100 µg/ml of the simian virus-40 large T antigen gene by Transfectam reagent (Promega) according to the manufacturer's protocol. The cells were maintained in culture for 2 days after transfection. Then they were dissociated with 0.25% trypsin-EDTA and reseeded onto the type IV collagen-precoated 48-well plates with fresh feeder cells. After passages 2 and 3, the transfection procedure was repeated, and the cells were expanded in the presence of feeder cells. After passage 3, the immortalized cells were no longer dependent on the presence of feeder cells and were maintained in K1 medium at 37°C in a 5% CO2-95% air humidified atmosphere.
The cells were stained by cytokeratin, but not byAlbumin Uptake Assay
Cells were exposed to serum-free DMEM containing BSA (5 mg/ml) at 37°C. Control cells were incubated on ice for measurement of nonspecific albumin uptake. After 90 min, the culture plates were placed on ice. Then the cells were scraped from the culture plates and lysed via sonication. After pH was adjusted to 7.4 with PBS (pH 6.0), insoluble material was removed by centrifugation. The supernatants were used for ELISA measurements (see BSA ELISA).BSA ELISA
Polyvinyl ELISA plates were coated with 100 µl of rabbit anti-BSA diluted 1:500 in PBS (pH 7.4) at 4°C overnight before experiments. After the plates were washed twice with PBS containing 0.05% Tween 20 (PBS-T), they were incubated with 100 µl of cell lysates for 2 h at room temperature. Nonspecific peroxidation sites were blocked for 30 min at room temperature with 3% H2O2. After repeated washings, the plates were incubated with 100 µl of biotinylated anti-rabbit BSA diluted 1:250 in PBS for 2 h at room temperature. After repeated washings, the plates were incubated with 1:1 avidin-biotinylated horseradish peroxidase for 1 h at room temperature. After repeated washings, the plates were incubated with 100 µl of azinobis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt peroxidase substrate (1 mg/ml), 0.1 M citric acid (pH 4.2), and 30% H2O2 (0.3 µl/ml) at room temperature for 30 min. The absorbance of each well was read at 405 nm using an automatic ELISA plate reader. A standard curve was plotted, and BSA concentration in each sample was calculated by comparison with a standard curve.Proximal Tubular Cell Culture and Experimental Procedure
Murine proximal tubular (mProx) cells were cultured in DMEM containing 10% heat-inactivated FBS, 100 U/ml penicillin, and 100 µg/ml streptomycin. Cultured cells from passages 4-30 were used for the experiments. Subconfluent cells were made quiescent by incubation with 0.1% FBS-DMEM for 24 h. Quiescent cells were incubated with various concentrations of fatty acid-free BSA in the experimental medium (DMEM with 0.1% BSA and 14 mM HEPES) for the indicated times at 37°C. For the experiments with inhibitors, cells were incubated with the indicated concentrations of U-0126 or SB-203580 for 60 min at 37°C before exposure to BSA. After incubation, cells were harvested for the determination listed below.Northern Blot Analysis
Total RNA (12 µg) was isolated by guanidinium and phenol extraction (TRIzol Reagent, GIBCO BRL, Grand Island, NY), electrophoresed on 1% formaldehyde-agarose gels, and transferred to a nylon membrane (Nytran, Schleicher & Schuell, Dassel, Germany). Mouse MCP-1 was labeled with [Immunoblot Analysis
Immunoblot analysis was performed as previously described (15). Briefly, proximal tubular cells were lysed in SDS sample buffer (62.5 mM Tris · HCl, pH 6.8, 2% SDS, 10% glycerol, 50 mM dithiothreitol, and 0.01% bromphenol blue). The cell lysates containing 40 µg of proteins in SDS sample buffer were electrophoresed on 12% SDS-polyacrylamide gels and electrotransferred to polyvinylidene difluoride membranes (Immobilon, Millipore, Bedford, MA). After the membranes were blocked, they were incubated with a 1:1,000 dilution of antiphospho-ERK, antiphospho-p38 MAPK, antiphospho-JNK, or antiphospho-IDNA Constructions and Transient Transfection
The pJECAT2.6 was a gift from Dr. J. M. Boss. The reporter construct contains DNA fragments for the six MCP-1/JE promoter fused to the coding region of the chloramphenicol acetyltransferase gene (20). To construct the luciferase reporter (MCP-1/JE-Luc), the MCP-1/JE promoter site constructions were subcloned into pGL3 vector (Promega) at MluI/XhoI sites. mProx cells (~1 × 106/assay) were transfected with 0.7 µg of theMCP-1 Measurement by ELISA
The culture media of proximal tubular cells on a 24-well plate were collected and stored atNuclear Extraction and Electrophoretic Mobility Shift Assay
Nuclear protein was prepared from proximal tubular cells as previously described (15). Electrophoretic mobility shift assays (EMSAs) were performed by incubation of 5 µg of nuclear proteins with 1 µg of poly(dI-dC) in binding buffer (20 mM HEPES, pH 7.9, 1.8 mM MgCl2, 2 mM dithiothreitol, 0.5 mM EDTA, and 0.5 mg/ml BSA) at room temperature for 20 min and reaction with [The coding strand sequences of the DNAs of interest were as
follows: 5'-GCACCCTGCCTGACTCCACCCCCCTGGCTTACAA-3' (AP-1/GC) and 5'-CCCGAAGGGTCTGGGAACTTCCAATACTGCCTCAGAATGGGAATTTCCACGCTCTTATCC-3' (B-1/
B-2).
Statistical Analysis
Values are means ± SD. Analysis of variance followed by Scheffé's test was used to determine significant differences in multiple comparisons. P < 0.05 was defined as statistically significant. ![]() |
RESULTS |
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Characterization of Immortalized mProx Cells
Albumin uptake into mProx cells. To ensure that our mProx cells would reabsorb albumin, as occurs in the normal kidney, the cells were incubated with 5 mg/ml BSA for 90 min at 37°C, and then cellular BSA was measured by ELISA (see METHODS). The cells showed about fivefold enhanced albumin reabsorption compared with control (0.247 µg albumin/mg protein at 37°C vs. 0.042 µg albumin/mg protein at 4°C). Approximately 75% of uptake was blocked by cold incubation, indicating that the majority of cellular albumin uptake was specific. These results also indicate that this cell line expresses a proximal tubular phenotype and is functionally similar to primary cultures.
Effect of BSA on MCP-1 mRNA Expression
We examined whether BSA stimulated the expression of MCP-1 mRNA in mProx cells. By Northern blotting, BSA (30 mg/ml) induced MCP-1 mRNA in a time-dependent manner from 1 h to a maximal stimulation at 6 h (Fig. 1A). The induction of MCP-1 mRNA by BSA was dose dependent, with a maximal stimulation at 30 mg/ml (Fig. 1B).
|
Activation of MAPKs and NF-B by BSA
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To define the kinetics of IB-
proteins involved in NF-
B
activation, we examined the phosphorylation and degradation of I
B-
. Exposure to BSA led to transient phosphorylation of
I
B-
in 1 h. In parallel, I
B-
is degraded and then
returned to control levels within 2.5 h. After 2.5 h,
phosphorylation and expression of I
B-
seemed to be increased
(Fig. 3).
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Effect of MAPK Pathway on BSA-Induced MCP-1 Expression
We next investigated the intracellular signaling pathways involved in BSA-induced MCP-1 expression. Because we clearly demonstrated that BSA activated ERK and p38 MAPK (Fig. 2), the effect of inhibitor of MEK (U-0126) or p38 MAPK (SB-203580) on expression of MCP-1 was examined. We first confirmed that albumin uptake was not affected by pretreatment with U-0126 (data not shown). Treatment with U-0126 partially suppressed BSA-induced MCP-1 mRNA expression. On the other hand, SB-203580 tended to inhibit BSA-induced MCP-1 mRNA, but this effect was not statistically significant (Fig. 4A). To further confirm the roles of ERK and p38 MAPK in MCP-1 expression, accumulation of MCP-1 protein in the medium was analyzed by ELISA. Consistent with the result of Fig. 4A, treatment with U-0126 suppressed BSA-induced MCP-1 protein in a dose-dependent manner. SB-203580 tended to suppress BSA-induced MCP-1 protein, but this effect was not statistically significant. The combination of U-0126 and SB-203580 suppressed BSA-induced MCP-1 protein, but these effects were not additive or synergistic (Fig. 4B). To elucidate the mechanism of transcriptional regulation of MCP-1 in mProx cells, the six MCP-1/JE promoter fusion reporter constructs, 2,724-bp fragment (
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Effect of the MAPK Pathway on BSA-Induced DNA Binding of NF-B
and AP-1
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Pretreatment of mProx cells with U-0126 attenuated the DNA binding
activity of AP-1 by BSA (Fig. 5B). DNA-binding activity of
NF-B was also inhibited by U-0126 (Fig. 5C).
Involvement of MAPK in BSA-Induced IB-
Degradation and
NF-
B Activation
|
To further confirm the involvement of ERK in the activation of NF-B,
we performed reporter assay using 5×NF-
B luciferase vector
(NF-
B-Luc). Mouse proximal tubule cells transfected with NF-
B-Luc
demonstrated an increase in luciferase activity on exposure to BSA
(Fig. 6B). When mProx cells were treated with 10 µM U-0126 before exposure to BSA, the luciferase activity was partially suppressed.
These results suggest that the ERK pathway is involved in the
activation of NF-B by BSA.
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DISCUSSION |
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Increasing evidence suggests that proteinuria itself
may mediate disease progression in chronic glomerulopathy, rather than simply reflect the severity of glomerular injury (3, 22). Although albumin was found to induce the transcription and
translation of MCP-1 in rat proximal tubular cells at
pathophysiologically relevant concentrations (31), signal
transduction pathways involved in the effect of albumin on MCP-1 have
not been fully characterized. In the present study, we demonstrated
that 1) albumin induced the expression of MCP-1 in mProx
cells, a newly established mouse proximal tubular cell line;
2) albumin induced the activation of ERK and the
phosphorylation and degradation of IB-
; 3) the inhibition of MEK with U-0126 reduced MCP-1 expression; 4)
U-0126 inhibited albumin-induced activation of DNA binding of AP-1 and NF-
B, the binding sites of which existed in the promoter region of
MCP-1; and 5) the transcriptional activity of NF-
B and
I
B-
degradation were inhibited by U-0126.
In the present study, ERK was significantly activated 5 min after
stimulation with BSA and returned to basal levels by 30 min in mProx
cells. A similar effect of albumin was observed in opossum kidney
proximal tubular cells, in which ERK was activated 1 min after
incubation with recombinant human serum albumin, reached maximal
activation at 5 min, and returned to basal levels by 30 min
(9). These results suggest that albumin is able to rapidly activate ERK in proximal tubular cells. Although BSA could also activate p38 MAPK in mProx cells, the MKK6-p38 stress kinase cascade was found to be critical for tumor necrosis factor--induced
expression of MCP-1 in human umbilical vein endothelial cells
(11). In the present study, the inhibitor for p38 MAPK
tended to suppress BSA-induced MCP-1 expression, but this effect was
not statistically significant. Thus further studies are needed to
clarify the involvement of p38 MAPK in the regulation of MCP-1.
We found that U-0126, an inhibitor of MEK, was able to inhibit
BSA-induced mRNA and protein expression of MCP-1 and MCP-1 reporter
activity in mProx cells. In addition, phosphorylation and degradation
of IB were also induced by BSA in mProx cells. Although albumin
overload induced MCP-1 expression through activation of NF-
B in rat
proximal tubular cells (32), we hypothesized that the
ERK-AP-1 and I
B-NF-
B pathways could be responsible for
albumin-induced expression of MCP-1. Indeed, the cooperative action of
NF-
B and AP-1 in interleukin-1
-induced MCP-1 gene expression was
suggested in human endothelial cells (19). The murine
MCP-1/JE gene contains two
B sites in the distal regulatory region
and one AP-1-binding site in the proximal regulatory region (20). We found that BSA could stimulate DNA binding of
AP-1 and NF-
B in the MCP-1 gene in mProx cells. As expected, U-0126 inhibited AP-1 induced by BSA. Interestingly, U-0126 also partially inhibited BSA-induced NF-
B-binding activity and NF-
B-dependent transcription as well as the degradation of I
B in mProx cells. These
results indicate that the ERK pathway interacts with the I
B-NF-
B
pathway after stimulation with BSA in mProx cells. This hypothesis is
supported by the recent findings in melanoma cells, in which
NF-
B-induced kinase (NIK) was found to regulate NF-
B activation
through a novel NIK-MEK-ERK-NF-
B signaling pathway in addition to
the classical NIK-IKK-I
B-NF-
B pathway (8).
Although further investigation is needed to elucidate the precise roles
of ERK, the present findings support the hypothesis that the ERK
pathway is involved in BSA-induced MCP-1 expression and suggest a
possible interaction between NF-B and ERK. This information could be
useful in the design of anti-inflammatory strategies to suppress not
only cell proliferation but also transcriptional activation of
cytokines in renal diseases.
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. Haneda, Dept. of Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan (E-mail: haneda{at}belle.shiga-med.ac.jp).
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 January 7, 2003;10.1152/ajprenal.00230.2002
Received 18 June 2002; accepted in final form 30 December 2002.
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