Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies suggest that proteolytic enzymes located within the glomerulus are involved in the degradation of extracellular matrix components. In the present investigation glomerular proteinase activities were followed in a variety of non-immune-mediated renal diseases as well as during different dietary manipulations. Azocaseinolysis was significantly reduced in the obese Zucker rat compared with lean littermates (pH 5.4:8.9 +/- 0.4 vs 11.4 +/- 0.7; pH 7.4:5.8 +/- 0.7 vs 9.3 +/- 0.6 arb. U/mg protein). When the glomerular proteolytic capacity was measured in old rats, again a significant decline in proteolysis was observed (pH 5.4:9.8 +/- 0.8 vs 17.7 +/- 0.8; pH 7.4:6.4 +/- 0.7 vs 11.7 +/- 0.5 arb. U/mg protein). In Goldblatt hypertensive rats the unclipped kidney, which is exposed to high blood pressure, revealed lower glomerular azocaseinolytic activity compared with the contralateral clipped kidney (pH 5.4:8.1 +/- 0.4 vs 12.9 +/- 0.5 arb. U/mg protein). In parallel, the cathepsin B content was also diminished in glomeruli from kidneys exposed to hypertension. When proteinases were followed in glomeruli from intact kidneys of rats fed protein-modified diets (fraction of casein 0.05, 0.20 or 0.60) a significant fall in the activities of cysteine proteinases, e.g. cathepsin B (casein 0.05:1,498 +/- 110 vs casein 0.60:914 +/- 84 microU/micrograms DNA), as well as metalloproteinases, e.g. collagenase (casein 0.05:233 +/- 14 vs casein 0.60:137 +/- 11 microU/micrograms DNA), occurred. These data indicate that in both early and late stages of glomerulosclerosis, proteolytic activities within the glomerulus tend to be reduced, which could allow extracellular matrix accumulation. Moreover, changes in dietary protein intake resulted in profound alterations of glomerular proteinases.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of glomerular proteinases in the evolution of glomerulosclerosis. 149 56

This study examines the amount of total collagen and its different fractions synthesized by cultured human glomerular epithelial and mesangial cells. Two quantitative techniques were used, namely estimation of proline (Pro) plus hydroxyproline (Hyp) present in the collagenase-sensitive proteins and ELISA or RIA of the different types of collagen. In addition, the pattern of collagen synthesis for both cell types was further examined using immunofluorescence methods and polyacrylamide gel electrophoresis. Glomerular epithelial cells synthesized mainly type IV collagen and it was, for the better part, cell-associated. Mesangial cells synthesized approx. 4-times more collagen than epithelial cells. Type I collagen was predominant, but there were also type IV and III collagens. Secreted and cell-associated collagens were present in roughly equivalent amounts. In both cell lines 10-14% of the newly synthesized collagen had been degraded within the cells. These results provide quantitative data on collagen synthesis by human glomerular cells in vitro and represent the first necessary stage before studying which factors mediate the development of glomerular sclerosis.
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PMID:Quantification of collagen synthesis by cultured human glomerular cells. 265 90

Nonobese diabetic (NOD) mice spontaneously develop immune-mediated insulin-dependent diabetes mellitus and nephropathy, providing an opportunity to study the early molecular events in a model of diabetic glomerulosclerosis. The expression of several genes coding for growth factors and extracellular matrix was examined in microdissected glomeruli, by the use of reverse transcription-competitive polymerase chain reaction, in diabetic NOD mice (mean duration of diabetes, 28.5 +/- 7 days) and age-matched nondiabetic NOD mice with normal glucose tolerance. The levels of mRNA coding for transforming growth factor-beta 1, tenascin, and laminin B1 increased 1.9-, 2.0-, and 1.7-fold, respectively, whereas platelet-derived growth factor (PDGF)-B, alpha 1(IV) collagen, 72-kd collagenase, alpha-smooth muscle actin, and beta-actin mRNA remained stable in the diabetic mice. The kidney advanced glycosylation end-products levels increased 2.1-fold in the diabetic mice, and the diabetic glomeruli showed an accumulation of tenascin and laminin but not of type IV collagen by immunofluorescence microscopy. There was no increase in cell number per glomerulus after the onset of diabetes, a finding consistent with stable PDGF-B and alpha-smooth muscle actin mRNA levels. These findings provide evidence that increased glomerular transforming growth factor-beta 1, but not PDGF-B, mRNA is associated with the up-regulation of tenascin and laminin expression after advanced glycosylation endproduct accumulation, early after the onset of diabetes.
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PMID:Overexpression of transforming growth factor-beta 1 mRNA is associated with up-regulation of glomerular tenascin and laminin gene expression in nonobese diabetic mice. 753 9

Oligosyndactyly mice (ROP Os/+) are a radiation-induced mutant strain with reduced glomerular number and increased glomerular size. We found that they develop glomerulosclerosis. At 3 mo, ROP Os/+ mice had diffuse mesangial expansion by light microscopy, whereas their +/+ littermates did not. Electron microscopic morphometry revealed a twofold increase in mesangial areas but no changes in the thickness of glomerular basal laminae. Mean glomerular volume was increased 1.8-fold. Cell number and thymidine labeling index were increased 1.3- and 2.4-fold, respectively. The amount of glomerular type IV collagen and tenascin but not laminin was increased by immunofluorescence microscopy. mRNA levels in microdissected glomeruli were measured by competetive reverse transcription-polymerase chain reaction and corrected for cell number. alpha 1-Chain type IV collagen and tenascin mRNAs were increased 3.2-fold and 1.8-fold, whereas laminin B1 mRNA levels were not. The levels of 72-kDa collagenase mRNA were increased 1.6-fold. Transforming growth factor-beta 1 mRNA levels were elevated 1.8-fold, but platelet-derived growth factor-B mRNA levels remained normal. This is the first analysis of glomerular molecular and cellular changes in a model of congenital nephron reduction.
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PMID:Molecular analysis of spontaneous glomerulosclerosis in Os/+ mice, a model with reduced nephron mass. 754 40

The present study was designed to assess whether expression of mRNA for extracellular matrix (ECM) components, metalloproteinases (MMP) and tissue inhibitor of metalloproteinases (TIMP) in glomeruli is affected by a low protein diet during the course of focal glomerulosclerosis (FGS). Puromycin aminonucleoside (PAN) was injected intraperitoneally in rats and the right kidney was removed on day 22. Nephrotic rats received successive intraperitoneal injections of PAN on days 27, 34, and 41. Control rats were subjected to a nephrectomy or a sham operation on day 22. Animals were divided into six groups. In group 1, the PAN-injected rats were fed a standard diet containing 22% protein. In group 2, the PAN-injected rats were fed a low protein diet containing 6% protein, starting on the same day as the first PAN injection. In group 3, the nephrectomized rats without PAN were fed a standard diet. In group 4, the nephrectomized rats without PAN were fed a low protein diet for the same period. In group 5, the sham operated rats were fed a standard diet. In group 6, the sham operated rats were fed a low protein diet for the same period. Rats were sacrificed on days 0, 60 or 80 after the initial PAN or saline injection. The percentage of sclerotic glomeruli in group 1 rats increased markedly with time, reaching 77% on day 80. The mRNA levels encoding for alpha 1(I), alpha 1(III), alpha 1(IV) collagen chains, laminin B1 and B2 chains, heparan sulfate proteoglycan (HSPG), MMP-2, TIMP-1 and TIMP-2 increased significantly as glomerulosclerosis progressed, whereas MMP-1 and MMP-3 mRNA levels were unchanged, and no MMP-9 mRNA was detected throughout the experiments. In group 2, the low protein diet reduced the prevalence of glomerulosclerosis and attenuated the increased mRNA expression for ECM components, MMP-2, TIMP-1 and TIMP-2 in FGS glomeruli. In groups 3 through 6, mRNA levels for ECM components decreased with age, whereas those for MMPs and TIMPs changed little throughout the experiments. Immunofluorescence studies revealed the accumulation of types I, III and IV collagens, laminin, and HSPG in the sclerotic area and low protein diet attenuated the accumulation of these proteins. These data suggest that glomerulosclerosis may result from an imbalance among ECM components, MMPs and TIMPs and that a low protein diet attenuates the otherwise increased levels of mRNA for ECM components, MMP-2, TIMP-1 and TIMP-2 in glomerulosclerosis.
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PMID:Low protein diet blunts the rise in glomerular gene expression in focal glomerulosclerosis. 793 7

Hyperlipidemia, especially hypercholesterolemia, may contribute to glomerulosclerosis as it does to atherosclerosis. Low density lipoprotein (LDL) stimulates the production of extracellular matrix by mesangial cells in culture as well as the proliferation of mesangial cells. This study was carried out to examine the effects of LDL on the type IV collagen (CIV) production by cultured rat mesangial cells (CRMC). Subconfluent CRMC monolayers which were grown in RPMI with 20% lipid-free fetal calf serum for 48 h were challenged with LDL (0, 50, 100, 150 and 200 micrograms/ml) for another 48 h. LDL was prepared from normal human plasma. Mesangial cell proliferation was examined by [3H]-thymidine uptake. Production of CIV was evaluated as the expression of CIV on the cell surface by flow-cytometric analysis. The collagen synthesis was measured by the [3H]-proline uptake. Total RNA was extracted from CRMC at 6 and 24 h of incubation with 150 micrograms/ml LDL, and Northern blotting and hybridization was performed with cDNAs for alpha 1-CIV, for 72-kD collagenase and for tissue inhibitor of metalloproteinase (TIMP)-2. The amount of total mRNA was corrected with beta-actin mRNA. Mesangial cell proliferation increased in all concentrations studied and had a peak value of 221% with 150 micrograms/ml of LDL. Expression of CIV increased by 30-60% in 100-200 micrograms/ml of LDL. Collagen synthesis also increased by 50-70% in 150-200 micrograms/ml of LDL. The mRNA ratio (procollagen alpha 1(IV)/beta-actin) increased to 133% at 24 h. The mRNA ratio (TIMP-2/beta-actin) increased to 137% at 24 h. mRNA ratios at 6 h showed no change.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of low density lipoprotein on type IV collagen production by cultured rat mesangial cells. 793 24

Transforming growth factor-beta (TGF-beta) is a prototypical multifunctional cytokine, with growth being only one of its many functions. Its receptors and actions are germane to almost every cell in the body involved in tissue injury and repair, and its effects are best understood in the context of a cellular response to a changing environment. The broad areas in which TGF-beta plays a crucial role include cell proliferation and extracellular matrix production. TGF-beta is a key regulatory molecule in the control of the activity of fibroblasts and has been implicated in several disease states characterized by excessive fibrosis. In the kidney, TGF-beta promotes tubuloepithelial cell hypertrophy and regulates the glomerular production of almost every known molecule of the extracellular matrix, including collagens, fibronectin, tenascin, and proteoglycans, as well as the integrins that are the receptors for these molecules. Furthermore, TGF-beta blocks the destruction of newly synthesized extracellular matrix by upregulating the synthesis of protease inhibitors and downregulating the synthesis of matrix-degrading proteases such as stromelysin and collagenase. As will be discussed, there is a strong body of in vitro and in vivo evidence suggesting that persistent overproduction of TGF-beta 1 in glomeruli after the acute inflammatory stage of glomerulonephritis causes glomerulosclerosis. TGF-beta may also be important in a variety of other chronic renal disorders characterized by hypertrophy and sclerosis, such as diabetic nephropathy. In this review we will attempt to offer a basic understanding of the cellular and molecular biology of TGF-beta and its receptors, with special focus on the role of the TGF-beta system in the kidney during development, growth, and disease.
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PMID:The emerging role of transforming growth factor-beta in kidney diseases. 802 63

Mesangial cell (MC) hyperplasia and accumulation of extracellular matrix are hallmarks of chronic glomerular disease. The present in vitro study examined the effects of cell density on growth, extracellular matrix formation, and protein synthesis of cultured rat MCs. A negative linear relationship was found between initial plating density and DNA synthesis per cell after 24 hours incubation in medium with 10% fetal calf serum (range: 1 x 10(3) to 7 x 10(5) MCs/2cm2, r = 0.996, P < 0.001). Enzyme-linked immunosorbent assay of the amount of fibronectin in the conditioned medium after 72 hours showed a negative relationship with increasing cell density. In contrast, the amount of cell-associated fibronectin increased to maximal values in confluent cultures, and no further increase was seen at supraconfluency. The relative collagen synthesis in the conditioned medium and cell layer--assessed by collagenase digestion after 5 hours [3H]proline pulse labeling--showed a similar pattern. Secreted collagen decreased with increasing cell density from 3.4% to 0.2% of total protein synthesis. In contrast, cell-associated collagen increased from 1.1% to 11.8% of newly synthesized protein until confluency followed by a decrease to 4.2% at supraconfluency. Specific immunoprecipitation of collagen types I, III, and IV revealed a significant (twofold) increase in collagen I synthesis per cell at confluency. Collagen III and IV synthesis was not affected by cell density. Specific protein expression in both the medium and cell layer were analyzed by two-dimensional polyacrylamide gel electrophoresis (150 to 20 kd, pI 5.0 to 7.0) after 20 hours steady-state metabolic labeling with [35S]methionine. Supraconfluent MCs displayed overexpression of 10, underexpression of four, new expression of five, and changed mobility of three different intracellular proteins. Of interest was the overexpression of two proteins (89 kd, pI 5.31 and 72 kd, pI 5.32) that were identified by immunoblotting as the stress proteins heat-shock protein 90 and glucose-related protein 78, respectively. The progressive increase of cell-associated fibronectin and collagens, particularly collagen type I, in confluent MCs resembles extracellular matrix accumulation in glomerular disease. The increased expression of stress proteins in supraconfluent MCs is of interest in view of the analogy between glomerulosclerosis and atherosclerosis in which stress proteins are expressed in high concentrations.
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PMID:Cell density modulates growth, extracellular matrix, and protein synthesis of cultured rat mesangial cells. 821 12

Some forms of glomerulonephritis (GN) in humans appear consequent to autoimmunity. Experimental autoimmune GN (EAG) has been described in sheep, but attempts to develop EAG in other mammals have resulted only in antibody and proteinuria but no GN. We have developed a model of EAG in an inbred mammalian species to further study pathogenetic mechanisms. We immunized Brown Norway (BN) and Wistar-Kyoto (WKY) rats with glomerular basement membrane (GBM) or collagenase solubilized GBM (csGBM). Circulating and bound anti-GBM antibody developed in all rats. Only interstitial nephritis occurred in BN rats despite amounts of glomerular and serum anti GBM antibodies similar to WKY animals. One hundred percent of WKY rats immunized with csGBM/acid developed reproducible severe GN at two to three weeks with proteinuria and decreased kidney function which progressed to glomerulosclerosis and interstitial fibrosis. Antigen in acid was a requisite for induction of EAG. EAG rats had positive tests for delayed type hypersensitivity, their T cells underwent antigen specific transformation, and T cells and macrophages were present histologically. Passive transfer of EAG serum to naive rats resulted in fixation to recipient GBM but no proteinuria or GN. This new model of EAG in rats appears dependent on genetic factors, may involve cellular immunity in pathogenesis, requires exposure of the nephritogenic antigen, and is highly similar to rapidly progressive GN in humans.
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PMID:Proliferative autoimmune glomerulonephritis in rats: a model for autoimmune glomerulonephritis in humans. 837 73

After in vivo administration of purified antibody against cultured mesangial cell (anti-MC IgG), glomerular basement membrane (GBM) was selectively bound. The glomerular bound anti-MC IgG exhibited a monospecificity for a 109-kDa antigen extracted from cultured mesangial cells and normal GBM. The antigen was not digestible by collagenase, heparitinase, or chondroitinase and was revealed by immunoelectron microscopy of a normal glomerular component to be predominantly distributed along the lamina rara externa of GBM and to be absent in mesangium. The ample expression of the antigen in puromycin aminonucleoside nephrosis implies that it represents a significant sclerotic material in glomerulonephritis. Abnormal production of GBM components by mesangial cells may play an important role in glomerulosclerosis.
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PMID:Coexpression of a novel glomerular basement membrane matrix material in mesangial cell culture and glomerulosclerosis. 854 99


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