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Renal-Electrolyte and Hypertension Division, Department of Medicine, and the Penn Center for the Molecular Studies of Kidney Diseases, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6144
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ABSTRACT |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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The core protein
of the proteoglycan decorin binds and neutralizes transforming growth
factor-
(TGF-). Activation of TGF- is crucial to tissue injury
in diabetic nephropathy, but it is not currently known whether decorin
plays a role in this disease. Mouse kidney cortex demonstrates more
than a twofold increase in decorin mRNA after 1, 2, 3, and 6 wk of
streptozotocin diabetes. Various mouse and rat renal cell types are
studied in culture under normal or high-glucose conditions. Mouse
glomerular mesangial and proximal tubular epithelial cells
constitutively express decorin, and high glucose (450 mg/dl) increases
decorin mRNA fourfold compared with 100 mg/dl glucose. Unlike rat
mesangial cells, rat glomerular epithelial and endothelial cells do not
constitutively express decorin, and no induction is observed in high
glucose. When mouse mesangial and proximal tubular cells are exposed to
TGF-1 (1 ng/ml), decorin mRNA is significantly decreased. Our
findings suggest that the increased decorin expression in the diabetic kidney may counteract the hypertrophic and prosclerotic effects of
increased TGF- levels and that a negative feedback loop may exist
between decorin and TGF-.
transforming growth factor-; diabetic nephropathy; glomerulus; endothelium; epithelium; rat
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INTRODUCTION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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EVIDENCE FOR A PATHOGENIC role of transforming growth
factor- (TGF-) in mediating the pathological features of diabetic kidney disease has been demonstrated in experimental models using in
vitro (31) and in vivo (21) approaches. Furthermore, kidney TGF-
mRNA and protein levels are upregulated in various human renal
diseases, including diabetic nephropathy (8, 23, 30).
Decorin is a small extracellular proteoglycan (92.5 kDa) comprising a
40-kDa core protein and a single chondroitin sulfate side chain. The
core protein binds and neutralizes extracellular TGF- and
antagonizes its prosclerotic effect (1). This property has been
exploited for therapeutic purposes. In experimental glomerulonephritis in the rat, administration of decorin alleviates extracellular matrix
accumulation and proteinuria (1). Glomerulonephritic rats transfected
with decorin cDNA show significantly decreased glomerular TGF-
levels and amelioration of proteinuria and the increased extracellular
matrix accumulation (7). Renal decorin mRNA and protein as well as
active TGF- levels are upregulated in experimental hydronephrosis in
the rat (4). In human biopsy specimens of various chronic renal
diseases, intrarenal decorin immunoperoxidase staining is significantly
enhanced, and decorin proved to be the best predictor among matrix
components of the severity of interstitial fibrosis and renal failure
(25). However, it is not currently known whether decorin plays any role
in noninflammatory kidney diseases such as diabetic nephropathy. Such
information would be important before considering the potential
therapeutic benefits of decorin in the future.
The aim of our present study was to evaluate the renal expression of
decorin in streptozotocin (STZ)-diabetic mice and to examine the effect
of high ambient glucose on the expression of decorin in glomerular
mesangial, epithelial, and endothelial cells as well as in proximal
tubular cells in culture. We were also interested in whether TGF-, a
cytokine that has a well-established role in the pathophysiology of
diabetic nephropathy and is itself upregulated in many in vitro and in
vivo models of renal diseases (15), can exert an effect on the
expression of the decorin gene, perhaps as a component of a negative
feedback loop.
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MATERIALS AND METHODS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Induction of Diabetes and Experimental Protocols
C57Bl female mice were fed a standard pellet laboratory chow and were provided with water ad libitum. Diabetes was induced in weight-matched 8-wk old mice (~20 g) by two consecutive daily intraperitoneal injections of STZ (200 mg/kg; Sigma Chemical, St. Louis, MO) dissolved in 10 mM sodium citrate, pH 5.5; controls were injected with buffer alone. A relatively high dose of STZ was needed to induce diabetes, because mice, as opposed to rats, are relatively resistant to the diabetogenic effect of the drug. On the same day that glucosuria was first present, up to 0.5 U NPH insulin (Eli Lilly, Indianapolis, IN) was administered to maintain the blood glucose concentration in the moderately hyperglycemic range of 250-400 mg/dl and to prevent ketonuria. In an additional group of diabetic mice, the insulin dose was increased up to 1.0 U NPH daily to maintain the blood glucose concentration below 140 to 180 mg/dl. Groups of diabetic and control mice were killed after 1, 2, 3, and 6 wk following the detection of glucosuria. Kidney cortex was excised, immediately frozen in liquid nitrogen, and stored at
70°C for subsequent
RNA extraction.
Cell Culture
Murine transformed and untransformed glomerular mesangial cells. Murine mesangial cells (MMC) were isolated by differential sieving from kidneys harvested from 8-wk old naive SJL/J (H-2S) mice (28). Cells were grown for 72 h in the presence of 50 mM D-valine (Sigma), replacing L-valine in the medium to exclude fibroblasts. Untransformed murine mesangial cells were designated uMMC. Subconfluent cells were transformed with a nonreplicating, noncapsid-forming strain of SV40 to establish a permanent cell line (28, 31) which was here designated tMMC. The cells maintain a differentiated phenotype as evidenced by the typical spindle-like appearance, positive staining for vimentin and desmin, production of several matrix components including collagens I and IV, and contraction in response to angiotensin II stimulation.Murine proximal tubular cells. The mouse cortical tubule cell line (MCT) was derived from microdissected proximal tubule segments of normal SJL mice and stabilized in long-term culture by SV40 transformation (6). The cells exhibit many phenotypic features of differentiated proximal tubular epithelial cells, including positive staining for cytokeratin, sodium-phosphate cotransport, and production of collagen IV and laminin.
Rat glomerular mesangial cells. Rat glomerular mesangial cells (RMC) were isolated from Sprague-Dawley rats by differential sieving and were characterized and grown in a manner similar to that described above for murine mesangial cells.
Rat glomerular endothelial cells. Rat glomerular endothelial cells (GEndC) cells were isolated and characterized as described elsewhere (29). The cells exhibit a cobblestone appearance when confluent in culture and stain positively with CD31 (PECAM-1), factor VIII, and lectin BSI (29).
Rat glomerular epithelial cells. Rat glomerular epithelial cells (GEpiC) are a gift of Dr. David J. Salant (Boston University) (16). The cells display cobblestone appearance, positive cytokeratin staining, junctional complexes by electron microscopy, secretion of basement membrane collagen and laminin, and expression of antigens characteristic of glomerular visceral epithelial cells.
Culture Media
The medium used for all cell types with the exception of GEpiC was DMEM (GIBCO-BRL, Gaithersburg, MD) supplemented with 100 µg/ml streptomycin, 100 U/ml penicillin, 2 mM glutamine, and 10% fetal calf serum (32). Cells were subcultured every 72 h and incubated in a humidified atmosphere of 5% CO2-95% air at 37°C. GEpiC were grown in standard K1 medium consisting of 47.5% DMEM, 47.5% Ham's F-10 (GIBCO), 4.9% NuSerum (Collaborative Research, Bedford, MA), and a 0.1% hormone mix described previously (5).Northern Hybridization
Cells were rested for 24 h in serum-free media, then carried for different time periods (24, 48, 72, and 96 h) in 0.5% fetal calf serum/DMEM containing either 100 mg/dl (5.6 mM) or 450 mg/dl (25 mM) D-glucose. RNA extraction from harvested cells or kidneys was performed as previously described (22, 28). For Northern blots, 25 µg total RNA was electrophoresed through a 1.0% agarose gel with 2.2 M formaldehyde. The RNA was electroblotted onto GeneScreen Plus nylon membranes (NEN Research Products, Boston, MA) and ultraviolet cross-linked. Integrity and equal loading of RNA samples were assessed by methylene blue staining of the transferred RNA (22). The membranes were prehybridized for 4 h at 65°C in a buffer containing 5× SSPE (1× SSPE = 149 mM NaCl, 10 mM NaH2PO4, 1 mM EDTA), 5× Denhardt's (50× Denhardt's = 1% Ficoll, 1% polyvinylpyrrolidone, 1% bovine serum albumin), 0.1% SDS, 100 µg/ml denatured salmon sperm DNA, and 50% (vol/vol) formamide. cDNA inserts were separated from their plasmids in low-melt agarose and labeled with 5 µCi [32P]dCTP (3,000 Ci/mmol; Amersham, Arlington Heights, IL) using hexamer primers. The decorin probe used was a 1,372-bp murine decorin cDNA segment (gift from Dr. Renato V. Iozzo, Thomas Jefferson University, Philadelphia, PA) (19). Blots were hybridized with 1 × 106 cpm/ml probe in hybridization buffer (same as prehybridization buffer except that 2× Denhardt's was used) for 16 h at 65°C. Membranes were washed for 5 min twice in 2× SSC (20× SSC = 3 M NaCl, 0.3 M sodium citrate, pH 7.0) at room temperature, then in 2× SSC with 0.1% SDS for 15 min at 65°C, followed by two 15-min high-stringency washes in 0.1 SSC and 0.1 SDS at 65°C. The membranes were then autoradiographed with intensifying screens at70°C for
1-4 days. Blots were stripped and subsequently rehybridized with
probes encoding the housekeeping gene glyceraldehyde-3-phosphate
dehydrogenase (GAPDH), 18S ribosomal RNA, or mouse ribosomal protein
L32 (mrpL32) (14) to account for small loading and transfer variations.
Exposed films were scanned with a densitometer (Hoefer Scientific
Instruments, San Francisco, CA), and relative RNA levels were calculated.
Statistical Analysis
Data are presented as the means ± SE. Comparison between two groups was performed by unpaired t-test. P < 0.05 was considered significant.| |
RESULTS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Diabetic Mice
To investigate the potential role of decorin in an in vivo model of diabetic kidney involvement, we evaluated decorin mRNA level in the kidney cortex of mice with STZ-induced diabetes. Figure 1A is a representative Northern blot demonstrating upregulation of the mRNA in the kidney cortex after 1-6 wk of established diabetes compared with nondiabetic control mice. Figure 1B summarizes the results of these studies. The stimulation of decorin mRNA in the diabetic kidney was rapid and sustained, with a twofold increase in the mRNA level after 1 wk of diabetes and up to 2.5-fold after 2, 3, and 6 wk. For instance, after 2 wk of diabetes, the relative decorin mRNA level was increased by 2.30 ± 0.50-fold (n = 8; P < 0.01 vs. control mice). Figure 1B also depicts the response to daily treatment of mice with a relatively high dose of insulin. With such a regimen, the blood glucose concentration was maintained below 180 mg/dl, and the decorin mRNA level was only 1.48 ± 0.63-fold that of control mice (n = 3, not significant). These findings are consistent with a stimulatory effect of the diabetic milieu on decorin expression rather than a direct effect of STZ.
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Mouse Mesangial Cells
To further delineate the significance of increased decorin gene expression in the diabetic kidney, we investigated different types of cultured renal cells under basal and high-glucose conditions. Decorin mRNA was found to be constitutively expressed in uMMC (Fig. 2A) as well as in tMMC (Fig. 2B). The decorin mRNA level was significantly increased by culturing either uMMCs or tMMCs in high-glucose media (450 mg/dl) compared with normal glucose media (100 mg/dl) (Fig. 2, A and B). For instance, stimulation by high-glucose media for 72 h caused a 4.09 ± 1.24-fold increase (n = 6) in the ratio of decorin mRNA level to that of GAPDH in tMMC (Fig. 2C).
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When exogenous TGF-1 at a concentration of 1 ng/ml was
added in the last 24 h of culture to tMMC, the basal as well as the high-glucose-stimulated level of decorin mRNA relative to that of
mrpL32 were reduced by more than 80%
(n = 3) (Fig.
3).
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Rat Glomerular Cells
We next investigated whether decorin expression is confined to mesangial cells within the glomerular compartment. We therefore analyzed different rat glomerular cell types that were available to us. As in mesangial cells derived from mouse, decorin mRNA was constitutively expressed in RMC but not in rat GEpiC or GEndC cells (Fig. 4). When cultured in high ambient glucose, no inducible decorin mRNA expression was observed in either the glomerular epithelial or endothelial cells (Fig. 4). On the other hand, culturing rat mesangial cells in high glucose for up to 96 h caused a 3.0-fold increase in the ratio of decorin message to that of GAPDH as compared with normal glucose (Fig. 4).
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Mouse Proximal Tubular Cells
We next investigated whether decorin expression is evident in nonglomerular cells in the kidney. MCT were examined because of the demonstrated increase in decorin mRNA in the kidney cortex of STZ-diabetic mice. When cultured under high-glucose conditions for 72 h, MCT cells exhibited increased decorin mRNA levels compared with normal glucose (Fig. 5); the ratio of decorin mRNA to that of mrpL32 was increased by 3.4-fold in high-glucose media (n = 3). As with mesangial cells, the addition of exogenous TGF-1 (1 ng/ml) for the
last 24 h of culture caused marked reduction in the decorin mRNA level
under both normal and high-glucose conditions (Fig. 5).
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Our study is the first to show that decorin mRNA levels are upregulated
in the kidney cortex of an animal model with diabetic renal
involvement. The only available evidence for a role of decorin in
diabetic kidney disease comes from in vitro experiments where decorin
mRNA expression and protein production were found to be increased in
human mesangial cells cultured under high-glucose conditions (26). Our
study expands on these findings by demonstrating that rat and mouse
mesangial cells also exhibit increased decorin mRNA levels when
cultured under high-glucose conditions. High glucose also exerted a
similar effect on mouse proximal tubular cells. We also show that
neither glomerular epithelial nor endothelial cells constitutively
express decorin mRNA as detected by Northern analysis, and there is no
induction of the message by high-glucose media. In this regard these
latter cells behave like bovine myocardial endothelial cells
(11). Furthermore, our studies demonstrate that exogenous TGF-1
exerts an inhibitory effect on decorin gene expression in
cultured mouse mesangial and proximal tubular cells.
In a previous study we demonstrated that the development of renal
hypertrophy in the STZ-diabetic mouse is characterized by increased
mRNA levels for TGF-1 and its primary signaling receptor, the type
II receptor (21). Increased renal TGF-1 mRNA level is also
a feature of models of spontaneous type 1 diabetes
mellitus such as the nonobese diabetic mouse and the BioBreeding
rat (22). In fact, the TGF- system appears to be
implicated in the development of diabetic renal hypertrophy since
neutralization of TGF- using repeated injections of anti-TGF-
antibody results in attenuation of kidney hypertrophy and the enhanced
extracellular matrix gene expression in STZ-induced diabetic mice (21).
Increased decorin gene expression by high ambient glucose, as
shown by our current study, may thus represent a mechanism to
counteract the injury produced by high-glucose-stimulated TGF-
(18, 28).
Since hyperglycemia in vivo and high ambient glucose in vitro stimulate
renal cell TGF- gene expression (18, 28) and our present studies
provide ample evidence that the same happens to decorin gene expression
in renal cells under similar circumstances, we also examined the effect
of TGF- alone on decorin mRNA abundance in murine
glomerular mesangial and proximal tubular cells. We found that addition
of TGF-1 downregulates decorin expression in these cells in culture.
The mechanism of this downregulation of decorin by TGF-1 needs to be
further investigated. Nevertheless, this inhibitory effect of TGF-1
on decorin gene expression suggests that the increased renal TGF-1
level in the diabetic state may participate in a negative feedback loop
involving decorin expression.
Regulation of decorin expression by TGF- may vary according to the
species and cell type being investigated. Our study demonstrating an
inhibitory effect of TGF-1 on decorin gene expression is not entirely in concordance with those of Border et al. (2) and Takeuchi et
al. (24), who found upregulation of decorin by TGF- in cultured rat
mesangial cells and murine osteoblast-like MC3T3-E1 cells,
respectively. Moreover, in other previous publications, TGF- was not
found to significantly change decorin expression in either cultured
fetal bovine tendinous tissue (17) or monkey arterial smooth muscle
cells (20). [It is noteworthy that the study by Robbins et al.
(17) actually found a slightly decreased decorin mRNA level in response
to treatment with exogenous TGF-]. However, in studies similar
to ours, Kahari et al. (9, 10) described TGF-1-induced
downregulation of decorin mRNA and protein level in cultured human skin
fibroblasts. Several other studies came to the same conclusion in
experiments on fibroblast cell cultures (3, 13, 27).
There are some data available regarding the regulation of decorin gene
expression. Mauviel et al. (12) demonstrated a 48-bp promoter segment
that functions as a bimodal regulator of decorin gene expression in
human dermal fibroblasts; tumor necrosis factor-
(TNF-)
downregulates and interleukin-1 upregulates decorin expression by
interacting with this site. Although TGF-1, like TNF-, decreased decorin mRNA by 60%, these investigators did not find a TGF-1 response element in their decorin promoter constructs (13). In the
experiments by Kahari et al. (9), the downregulating effect of TGF-
on decorin was prevented by dexamethasone. Clearly, much work is needed
to delineate the mechanism by which TGF- modulates decorin
expression in various cell types.
In the study by Wahab et al. (26) on human mesangial cells cultured
under high-glucose conditions, decorin mRNA levels were essentially
unchanged after 7 days, and the maximum upregulation of the decorin
message was described after 21-28 days; TGF-1 mRNA was
maximally stimulated at 7 days and less elevated after 21-28 days
(26). These findings are consistent with a downregulating effect of
TGF- on decorin expression and support our results in rat
untransformed mesangial cells, where we found no increase in decorin
mRNA after 48 h but significant increase after 96 h of high-glucose
exposure. These results also argue for a TGF-/decorin counterregulatory mechanism.
We conclude that the diabetic state is not a deficiency state as far as
the renal expression of decorin is concerned. The increased renal
cortical expression of decorin in STZ-diabetic mice likely reflects an
upregulation of decorin message in both glomerular mesangial as well as
in proximal tubular epithelial cells. Hyperglycemia per se is a
sufficient stimulus for the increase in the decorin mRNA level in these
cell types. Given the known TGF- binding properties of decorin and
the role that TGF- plays in mediating renal hypertrophy and matrix
accumulation in diabetes, our current findings suggest that increased
decorin production in models of diabetic renal disease may represent a
mechanism by which renal cells counteract the injury that is produced
by high-glucose-stimulated TGF- levels. Moreover, TGF- itself
downregulates the decorin message in mesangial and proximal tubular
cells, perhaps as a component of a negative feedback loop (see Fig.
6), and this adds a further dimension of
complexity to the multifaceted interplay of factors likely responsible
for the cellular injury in diabetic nephropathy. Future studies will be
needed to examine whether decorin knockout mice can develop more severe
diabetic lesions in the kidney and whether supplementation of exogenous
decorin will be of any benefit in the management of diabetic kidney
disease.
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ACKNOWLEDGEMENTS |
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We thank Dr. David J. Salant (Boston University) for the gift of glomerular epithelial cells, Dr. Renato V. Iozzo (Thomas Jefferson University, Philadelphia, PA) for the murine decorin cDNA, Mark Ericksen and Jia Guo for technical support, and Drs. Brenda B. Hoffman and Dong Cheol Han for useful discussion.
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FOOTNOTES |
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This study was supported in part by a fellowship grant from the Juvenile Diabetes Foundation International (A. Mogyorosi), National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-44513 and DK-45191 (to F. N. Ziyadeh), and the DCI-RED Fund.
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. §1734 solely to indicate this fact.
Address for reprint requests: F. N. Ziyadeh, Renal-Electrolyte and Hypertension Division, Univ. of Pennsylvania, 415 Curie Boulevard, 700 Clinical Research Bldg., Philadelphia, PA 19104-6144.
Received 7 April 1998; accepted in final form 13 August 1998.
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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