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Department of Cardiovascular Pharmacology, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania 19406
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade the extracellular matrix (ECM). The membrane-type matrix metalloproteinases (MT-MMPs) are a new family of MMPs that differ from other MMPs in that they have a transmembrane domain that anchors them to the cell surface. MT-MMPs have been shown to function as receptors and activators for other MMPs and to localize extracellular matrix proteolysis at the pericellular region. Here we report on mRNA and protein expression of the fifth human MT-MMP (MT5-MMP), a 64-kDa protein that is capable of converting pro-MMP-2 to its active form, in human kidney as well as its upregulation in diabetes. We also demonstrate upregulation of the active form of MMP-2 in kidney samples from patients with diabetes. Through immunohistochemistry, MT5-MMP expression was localized to the epithelial cells of the proximal and distal tubules, the collecting duct, and the loop of Henle. Furthermore, the tubular epithelial cells that expressed MT5-MMP were associated with tubular atrophy. Because renal tubular atrophy is a significant factor in the pathogenesis of diabetic nephropathy and renal failure and the molecular mechanisms regulating this process remain unknown, it is hypothesized that the elevated expression of MT5-MMP contributes to the activation of pro-MMP-2, which participates in the remodeling of the proximal and distal tubules as well as in the collecting duct. These results provide the first evidence of the expression of a MT-MMP in diabetes and suggest a novel role for MT5-MMP in the pathogenesis of renal tubular atrophy and end-stage renal disease.
atrophy; extracellular matrix; protease; remodeling
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THICKENING OF THE GLOMERULAR and tubular basement membranes, expanded mesangial matrix, and tubulointerstitial fibrosis are hallmarks of diabetic nephropathy (9). There is also a degree of tubular atrophy that takes place as diabetes proceeds into end-stage renal disease (13). This atrophy is associated with high proliferative activity of tubular epithelial cells and modulation of the basement membrane (13). Also, it has been suggested that interstitial, rather than glomerular, mechanisms may be important in progressive loss of renal function (3, 13, 14). Changes in the tubulointerstitial compartment include expansion of the tubular basement membrane, alterations of extracellular matrix (ECM) in the interstitium, interstitial cell proliferation, inflammatory cell influx, and epithelial cell apoptosis (3, 13, 14, 16, 23). Furthermore, changes in the ECM have been shown to modulate tubular epithelial cell function such as cell proliferation (11) and atrophy (13).
Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade the ECM and are implicated in numerous pathological conditions, including atherosclerosis, inflammation, tumor growth, and metastasis (20, 26). The membrane-type matrix metalloproteinases (MT-MMPs) are a new family of MMPs. The MT-MMPs differ from other MMPs in that they have a transmembrane domain that anchors them to the cell surface. Like most of the MMPs, however, the MT-MMPs consist of four characteristic domains including a signal peptide for transport from the cell; a propeptide that renders the enzyme inactive until processed by a cysteine-switch mechanism; a catalytic domain containing a zinc binding site; and a hemopexin-like domain that serves as an inhibitor binding site (12, 15, 17, 18, 21, 22, 25). MT-MMPs have been demonstrated to function as receptors and as activators for other MMPs and serve to localize extracellular matrix proteolysis at the pericellular region (1, 21, 22). Some of the MT-MMPs have also been shown to cleave ECM molecules directly (8, 24). They have been demonstrated to play a role in metastasis and have been identified in numerous carcinomas (5, 10, 12, 15, 18, 21). Furthermore, it has been suggested that MT-MMPs contribute to the infiltration of inflammatory cells such as T cells into tissues, and it can be speculated therefore that MT-MMPs are likely to be involved in a host of diseases in which an inflammatory response is evoked (6).
Thus far, five novel human MT-MMPs have been identified in the literature (12, 15, 18, 21, 22, 25). Here we report on mRNA and protein expression of the fifth human MT-MMP (MT5-MMP) in human kidney. MT5-MMP has recently been identified in the literature as a 64-kDa protein that is capable of converting pro-MMP-2 to its active form (12, 17). MT5-MMP was identified in a brain cDNA library and, by Northern blot, has been localized in normal brain and in brain tumors including astrocytomas and glioblastomas (12). The results of the present study demonstrate MT5-MMP mRNA and protein expression in kidney and its upregulation in diabetes. Results also show elevated MMP-2 protein and enzyme activity in kidney samples from patients with diabetes. These results provide the first evidence of the expression of an MT-MMP in diabetes and suggest a novel role for MT5-MMP in the remodeling of the proximal and distal tubules as well as in the collecting duct and the loop of Henle. As MMPs are capable of modulating the tubular basement membrane and the tubulointerstitium, it is hypothesized that remodeling of the epithelial cell basement membrane, via MT5-MMP and MMP-2, contributes to the tubular atrophy that occurs in diabetic nephropathy and end-stage renal failure.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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TaqMan Quantitative PCR Analysis
Oligonucleotides for TaqMan PCR assay.
Table 1 shows the nucleotide sequences of
the oligonucleotide hybridization probes and primers used. These were
obtained from PE Applied Biosystems, a division of PerkinElmer (Foster City, CA). The primers of MT5-MMP were designed from the 3'-UTR region
of the gene using Primer Express Software (PE Applied Biosystems).
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TaqMan quantitative PCR assay.
Multiple tissue cDNAs were obtained from Clontech Laboratories (Palo
Alto, CA). These cDNAs were pooled from multiple donors for each
tissue. The number of samples represented for each tissue ranged from 1 to 550 (heart, n = 8; brain, n = 2;
placenta, n = 7; lung, n = 2; liver,
n = 1; skeletal muscle, n = 27; kidney, n = 8; pancreas, n = 20; spleen,
n = 6; thymus, n = 9; prostate, n = 20; testis, n = 19; ovary,
n = 7; small intestine, n = 32; colon,
n = 20; peripheral blood leukocyte, n = 550). TaqMan PCR was performed according to the manufacturer's
specifications (PE Applied Biosystems). Briefly, a master mix was made
containing TaqMan buffer A, MgCl2, dNTPs,
AmpErase UNG, and AmpliTaq Gold polymerase. To this mixture was added 5 µl (1 ng) of cDNA and either MT5-MMP primers (400 nM) and probe (200 nM) or 
-actin primers (200 nM) and probe (100 nM). The PCR reaction
was carried out in duplicate tubes in a TaqMan LS-50B PCR detection
system (PE Applied Biosystems) for 40 cycles.
-actin housekeeping
gene expression, yielding a value referred to as the "delta threshold
count." The tissue with the highest delta threshold count was
designated as having a relative copy number of one. The difference
between the tissue with the highest delta threshold count and any other
tissue was calculated and called "n." This n
value was used to calculate the relative copy number of a given tissue
(that is, relative copy number is equal to 2n).
The relative copy numbers for the tissues analyzed were utilized to
compare expression differences among tissues.
Statistical comparisons of relative copy numbers for each tissue were
based on the multiple cDNA samples per tissue (n = 1-550) run in quadruplicate. A Kruskal-Wallis one-way analysis of
variance was performed, followed by individual Mann-Whiney
U-test comparisons among tissues. Data were considered
significant if P < 0.05.
To confirm that the identity of the PCR products generated for TaqMan
analysis was in fact MT5-MMP, Southern analysis was conducted. The PCR
product (5 µl) from each tissue sample was electrophoresed on a 2.5%
agarose gel and then transferred to a nylon membrane (GeneScreen plus;
NEN Life Science Products). The membrane was prehybridized for 2 h
at 42°C with denatured ssDNA in standard buffer (50% deionized
formamide, 1.5 M NaCl, 1% SDS, 10% dextran sulfate) and then
hybridized with a MT5-MMP (1,100-bp fragment generated from an ApaI
restriction digest) cDNA probe labeled with [32P]dCTP
using random-priming synthesis (T7 QuickPrime; Pharmacia Biotech).
Hybridization was conducted overnight at 42°C with 1 × 109 cpm/µg denatured radiolabled probe in standard
buffer, where cpm is counts per minute. The membrane was washed under
low-stringency conditions in 1× standard sodium citrate (SSC), 0.1%
SDS at 25°C, followed by a high-stringency wash in 0.1× SSC, 0.1%
SDS for 30 min at 55°C. Hybridization signals were detected by
conventional X-ray autoradiography (Hyper film; Amersham Life Science)
and phosphorimaging (Storm 860, Molecular Dynamics). The resultant predicted size for the MT5-MMP PCR product was 85 bp.
Multiple-Tissue Western Blot Analysis
Human tissue extracts prepared from the liver, lung, kidney, skeletal muscle, heart, brain, spleen, testis, ovary, and placenta were purchased from Clontech Laboratories. The samples were provided in Laemmli buffer containing 62.5 mM Tris, pH 6.8, 2% SDS, and 5% glycerol and were reduced with-mercaptoethanol and heat denatured at 100°C for 3 min. The samples were evaluated for MT5-MMP expression by Western blot analysis. Briefly, samples (50 µg each) were resolved by electrophoresis through a 10% polyacrylamide gel and then
transferred to a nitrocellulose membrane with a Bio-Rad semidry
transfer apparatus (Bio-Rad, Hercules, CA). Unoccupied binding sites
were blocked overnight at 4°C with 5% nonfat powdered milk in a 0.1 M Tris · HCl buffer, pH 8.0, containing 1.5 M NaCl and 0.5%
Tween-20 (TBST). A rabbit polyclonal primary antibody directed against MT5-MMP (generated against amino acid sequence CNQKEVERRRKERRL located
in the coding region of MT5-MMP), diluted 1:5,000 in TBST, was then
added to the membrane and allowed to incubate for 1 h at 25°C.
The membrane was washed three times, 15 min each, with TBST, incubated
for 30 min with a goat anti-rabbit IgG secondary antibody conjugated to
horseradish peroxidase (Bio-Rad), and diluted 1:5,000 in TBST. The
membrane was washed as above, and the blot was developed by using the
enhanced chemiluminescence method (Amersham, Arlington Heights, IL)
according to the manufacturer's instructions.
Preparation of Kidney Tissue Extracts
Human kidney tissues from diabetic and nondiabetic individuals were obtained from the Anatomic Gift Foundation (Phoenix, AZ). Gender, age, and serum creatinine levels of the patients are described in Table 2. To analyze protein expression in these kidney tissues, protein extracts of the tissues were prepared. To prepare the tissues for extraction, they were first weighed and then minced into 1-mm3 pieces. The minced tissues were incubated in an extraction buffer consisting of 0.5% Triton X-100 (Sigma, St. Louis, MO) in PBS containing 0.01% sodium azide while being gently rotated at 4°C for 18 h. The concentration of the initial extraction mixture for each tissue sample was normalized to 400 mg/ml. After the extraction was complete, the samples were centrifuged at 3,500 rpm for 15 min at 4°C, and the supernatants were collected. The supernatants were then centrifuged at 14,000 rpm for 15 min at 4°C to clear the lysates further. Aprotinin (Sigma) was added to each extract to a final concentration of 3 U/ml. To check the quality of the extraction, samples of each extract prepared were analyzed by SDS-PAGE (10% polyacrylamide) in which the gel was stained with 0.25% Coomassie brilliant blue 250 (Sigma).
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Western Blot Analysis
To investigate MT5-MMP and MMP-2 protein expression in kidney tissue extracts (n = 6/condition), samples were normalized for protein concentration by using a DC Protein Assay (Bio-Rad) and prepared for Western analysis as described above, except that only 30 µg of total protein were used. As control standards, recombinant pro-MT5-MMP and pro and active MMP-2 were included on each respective blot. Also, for Western analysis of MMP-2 expression, a mouse monoclonal anti-MMP-2 primary antibody (2 µg/ml, clone 42-5D11, Oncogene Research Products, Cambridge, MA) and a goat anti-mouse IgG secondary antibody (1:5,000, GIBCO-BRL, Bethesda, MD) were used. The levels of intensity of each band relative to background were determined and quantitated with a Molecular Dynamics densitometer (Molecular Dynamics, Sunnyvale, CA). Data were expressed as means ± SE. For statistical analysis of MT5-MMP and MMP-2 expression, Student's t-test for unpaired data was used. Statistical significance was accepted when P < 0.05.Immunohistochemistry
Human kidney tissue (cortex and medulla) from four insulin-dependent diabetic and four nondiabetic patients was analyzed for MT5-MMP protein expression by immunohistochemistry. Formalin-fixed, paraffin-embedded, 4-µm-thick serial sections of cortex and medulla were obtained from Clinomics Laboratories (Pittsfield, MA). Staining was conducted by Clinomics using the Ventana Medical Systems ES System. Briefly, sections were deparaffinized in xylenes and rehydrated in graded alcohols and distilled water. Endogenous peroxidase was quenched with 0.3% H2O2. Nonspecific immunoglobulin binding sites were blocked with normal goat serum for 16 min, and the sections were then incubated with a rabbit polyclonal primary antibody directed against MT5-MMP for 32 min at room temperature. As a negative control, serial sections were treated with primary antibody that was preincubated with MT5-MMP protein (5-fold molar excess, overnight at 4°C). The sections were then stained by using the avidin-biotin-peroxidase method. The reaction was visualized with 3,3'-diaminobenzidine (DAB) as substrate. Sections were counterstained with Gill's hematoxylin solution, dehydrated in graded alcohols and xylenes, mounted, and then examined by light microscopy by using an Olympus IX70 microscope. Alternating sections from each kidney were also stained with hematoxylin and eosin (H&E).MMP-2 Activity ELISA
MMP-2 activity was quantitated with a human MMP-2 Activity ELISA System (Amersham Pharmacia Biotech, Piscataway, NJ) according to the manufacturer's instructions. Briefly, protein extracts, normalized in assay buffer [0.03 M phosphate buffer, pH 7.0, containing 0.1 M NaCl2, 1% (wt/vol) BSA, and 0.01 M EDTA], were incubated for 2 h at room temperature in microtitre wells coated with anti-MMP-2 antibody. Components of the extract other than MMP-2 were removed with four rinses in wash buffer (0.01 M phosphate buffer, pH 7.5, containing 0.05% Tween 20). Peroxidase-labeled Fab' antibody to MMP-2 was added to the wells for 1 h at room temperature. After excess peroxidase conjugate was removed with four rinses in wash buffer, the amount of peroxidase bound to each well was determined by the addition of 3, 3', 5, 5'-tetramethylbenzidine (TMB)/hydrogen peroxide in dimethylformamide (20%, vol/vol). The reactions were stopped with the addition of 1 M sulphuric acid, and the plate was read at 450 nm in a SPECTRAmax 250 Microplate Spectrophotometer (Molecular Devices, Sunnyvale, CA). The concentration of active MMP-2 in each sample was determined by interpolation from a standard curve using SOFTmax PRO software (Molecular Devices). Data were expressed as means ± SE. For statistical analysis of MMP-2 activity, Student's t-test for unpaired data was used. Statistical significance was accepted when P < 0.05.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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MT5-MMP mRNA Expression in Human Brain, Kidney, and Pancreas
The expression of MT5-MMP mRNA was analyzed by TaqMan quantitative PCR analysis (Fig. 1). cDNA samples from human heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon, and peripheral blood leukocytes were evaluated for MT5-MMP copy number relative to-actin. The results showed that
significant MT5-MMP mRNA expression was detected in brain, kidney, and
pancreas (Fig. 1A). Visualization of the MT5-MMP PCR
products on an agarose gel as well as Southern analysis of the PCR
products using a probe specific for MT5-MMP revealed a single band of
85 bp in all tissue samples determined to express MT5-MMP by TaqMan
analysis (Fig. 1B). Characteristic of the high sensitivity
of Southern blot analysis, relative to PCR analysis, MT5-MMP mRNA
expression was also detected in additional tissues, albeit at very low
levels (Fig. 1B).
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MT5-MMP Protein Expression in Human Kidney
MT5-MMP protein expression was evaluated in various human tissue extracts by Western blot. The results demonstrated that MT5-MMP protein was detected only in kidney (Fig. 2). Notably, two bands were detected. The molecular mass of the top band was ~64 kDa, in agreement with the predicted size of pro-MT5-MMP (17), and the molecular mass of the bottom band was ~58 kDa, presumably the active form of MT5-MMP. It should be noted that mRNA and protein expression are not always directly correlated, as was the case here in which MT5-MMP mRNA expression was detected in brain and pancreas but protein expression was not detected.
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Upregulated MT5-MMP Protein in Kidney Samples From Diabetic Patients
Because MT5-MMP protein was detected in normal human kidney, the possibility of further upregulation of MT5-MMP in kidney disease was investigated. Kidneys from nondiabetic and diabetic patients (n = 6/condition, Table 2) were analyzed by Western blot for MT5-MMP protein expression (Fig. 3A). The results demonstrated that MT5-MMP protein expression, in the active form, was significantly upregulated 22-fold (P < 0.02) in diabetic kidney samples (Fig. 3B).
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Upregulated MT5-MMP Protein in Cells of the Proximal and Distal Tubules and Collecting Ducts in Kidney From Diabetic Patients
Tissue samples from renal cortex (n = 4/condition) and renal medulla (n = 4/condition) of nondiabetic and diabetic patients were evaluated by immunohistochemistry. The results indicated that MT5-MMP was highly expressed in the epithelial cells of the proximal and distal convoluted tubules in the cortex (Fig. 4, A and B) as well as in the collecting duct and loop of Henle of the medulla (Fig. 5, A and B). Furthermore, tubular atrophy was noted in the diabetic kidney samples (Fig. 5, A and B). There was no MT5-MMP expression detected in the glomeruli (Fig. 4). Also, there was no appreciable staining for MT5-MMP in the nondiabetic kidney samples (Figs. 4 and 5, C and D). Additionally, no significant staining for MT5-MMP was observed in serial sections of diabetic kidney samples in which the primary antibody was preincubated and blocked with MT5-MMP protein (Figs. 4 and 5E).
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Elevated MMP-2 Protein and Enzyme Activity in Kidney Samples from Diabetic Patients
MMP-2 protein and enzyme activity were evaluated in kidney samples obtained from nondiabetic and diabetic patients (n = 6/condition) by Western blot and by an activity-based ELISA. The ELISA is specific for measuring MMP-2 enzyme activity only. The results generated by Western blot demonstrated significant elevation of MMP-2 protein of the active form (3.8-fold, P < 0.01) in kidney samples from diabetic patients compared with samples from nondiabetic patients (Fig. 6). As demonstrated by the activity-based ELISA, MMP-2 activity was also significantly elevated (6-fold, P < 0.05) in kidney samples from diabetic patients compared with samples from nondiabetic patients (Fig. 7).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In the present study, it is demonstrated that MT5-MMP mRNA and protein are expressed in the kidney and that expression is increased dramatically in patients with diabetes. Also, expression of MT5-MMP correlates with elevated MMP-2 enzyme activity. Furthermore, the data indicate that the induction of MT5-MMP protein expression occurs primarily in the epithelial cells of the proximal and distal tubules, the collecting duct, and the loop of Henle, and this supports the growing evidence that interstitial mechanisms are involved in the progressive renal damage often associated with diabetes.
The ECM in the kidney, as in other organs, can affect cell function in addition to contributing to the structural integrity of the tissue. In renal disease, for example, the modulation of the ECM contributes to tubular epithelial cell proliferation (11) and atrophy (13). It has been suggested that the tubular basement membrane mediates communication between epithelial cells and fibroblasts, and it has been demonstrated that components of the basement membrane such as laminin and collagen IV modulate signaling events between these two cell types (11). Qualitative and quantitative changes in the basement membrane occur in renal disease, suggesting that modulation of the basement membrane components contribute to pathological changes in the tubulointerstitium, in part, by altering tubular epithelial cell function (11, 14). MMP-2 is a proteolytic enzyme that degrades components of the basement membrane including laminin, collagen IV, and fibronectin (20), and immunolocalization of this enzyme has been detected in interstitial fibroblasts and epithelial cells of rat kidney (7). Proteolytic products of the basement membrane such as laminin and collagen IV fragments stimulate proliferation of epithelial cells (2, 27), and enhanced tubuloepithelial cell proliferation has been associated with elevated epithelial cell atrophy (13). Also, it has been demonstrated by Frisch and Francis (4) that disruption of epithelial cell-matrix interactions induces apoptosis. Furthermore, Pullan et al. (19) have shown in the mammary gland that apoptosis is suppressed in epithelial cells when they are adherent to their basement membrane. However, during mammary gland involution, cell loss due to apoptosis coincides with MMP expression, basement membrane degradation, and cell detachment. Notably, Park et al. (16) have demonstrated that detachment from the ECM induces apoptosis in kidney collecting duct cells. Furthermore, Thomas et al. (23) have correlated epithelial cell apoptosis, which may contribute to tubular atrophy, with the progression of renal damage. Thus it has been suggested that tubulointerstitial damage is a more consistent predictor of functional impairment rather than glomerular damage (14).
MT5-MMP has recently been identified in the literature as a new member of the growing MT-MMP family and has been demonstrated to convert pro-MMP-2 to its active form (12, 16). The pro form of MMP-2 is not catalytically active until its propeptide is cleaved off, and MT-MMP-mediated cleavage of the propeptide is one means of MMP-2 activation. Our results show elevated expression of active MMP-2 enzyme in kidney from diabetic patients. It is hypothesized that the elevated expression of MT5-MMP contributes to the activation of pro-MMP-2, which participates in the remodeling of the proximal and distal tubules as well as in the collecting duct. By immunohistochemistry, the expression of MT5-MMP protein correlated with epithelial cells in atrophied tubules. Renal tubular atrophy is a significant factor in the pathogenesis of diabetic nephropathy and renal failure, but the molecular mechanisms regulating this process remain unknown. It is hypothesized that the expression of MT5-MMP along with MMP-2 plays an important role in the remodeling of the basement membrane associated with the epithelial cells of the proximal and distal tubules and the collecting duct of the diseased kidney. Furthermore, the colocalization of MT5-MMP to sites of basement membrane remodeling suggests a potential role for this molecule as a receptor for and/or modulator of MMP-2 activity. We speculate that during diabetic nephropathy, MMP-mediated remodeling of the basement membrane contributes to epithelial cell detachment from the basement membrane, contributing to apoptosis of tubular epithelial cells and tubular atrophy. These events play an important role in the pathogenesis of renal tubular atrophy and end-stage renal disease, ultimately causing nonfunctional renal tubules in the kidney.
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ACKNOWLEDGEMENTS |
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The authors are grateful for the generosity of Dr. Nicholas Laping and Ms. Barbara Olsen in providing us with the kidney tissue samples for ELISA and Western blot analyses and to John Martin for help in making the antigenic peptides used for antibody production. We also thank Dr. David Brooks for helpful discussions during the writing of this manuscript.
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FOOTNOTES |
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Address for reprint requests and other correspondence: A. M. Romanic, GlaxoSmithKline Pharmaceuticals, Dept. of Cardiovascular Pharmacology, 709 Swedeland Rd., King of Prussia, PA 19406 (E-mail: anne_romanic-1{at}sbphrd.com).
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 7 September 2000; accepted in final form 17 April 2001.
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TOP
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
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