UMLS:C0011881 - FACTA Search

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Query: UMLS:C0011881 (diabetic nephropathy)
10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A monoclonal antibody (MCA IV-1) has been developed to a determinant of the high molecular weight fractions of human placental collagen, present also in bovine lens capsule and glomerular basement membrane type IV collagens. This unique determinant is pepsin and collagenase resistant and is apparently distinct from the alpha 1(IV) and alpha 2(IV) helical peptides. As part of the high molecular weight molecules, the determinant is located in a region additively deformable by reduction and sodium dodecyl sulfate denaturation. However, when a 20-kilodalton, largely collageneous, fragment containing this determinant is separated from the larger fraction by 37 degrees C collagenase treatment, the determinant is insensitive to reduction or sodium dodecyl sulfate denaturation. Immunohistologic analysis and comparison with a polyclonal antibody to type IV collagen shows a marked selectivity of localization in the glomerular basement membrane. MCA IV-1 reacts in the inner aspect of the glomerular basement membrane but primarily in the mesangium, where it selectively expands in diabetic nephropathy. Tissue selectivity is also evident in lens and corneal basement membrane.
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PMID:Monoclonal antibody to type IV collagen with selective basement membrane localization. 636 14

Abnormalities in extracellular matrix degradation may play a pathogenetic role in diabetic nephropathy. Cultured renal mesangial cells are known to synthesize increased amounts of matrix proteins when incubated in high glucose media (e.g., 30 mmol/l). However, the effect of glucose loading on degradative enzymes is unknown. Primary cultures of rat mesangial cells were grown until confluent in the presence of fetal calf serum (FCS) and insulin (0.67 U/ml). Cells were then cultured for 7 days in plastic wells in either 10 or 30 mmol/l glucose media containing neither FCS nor insulin. Collagenase activity in media were determined by zymography and quantitative spectrofluorometry. Cathepsin B and D activities in cell extracts were measured by spectrofluorometry (using the fluorescent substrate Z-Arg-Arg-7-amido-4-methylcoumarin) and 125I-labeled hemoglobin digestion, respectively. Gelatin-degrading activity of live mesangial cells was also determined. mRNA levels for collagenase IV, cathepsin B, and cathepsin D were determined by Northern analysis. A major band of collagenase activity with a molecular size of 72 kDa was observed in all mesangial cell media. Exposure of cells to high glucose media resulted in significant reductions in collagenase and cathepsin B activities as well as impairment in gelatin-degrading activity. Collagenase IV and cathepsin B and D mRNA levels were also decreased by glucose loading. To exclude the possibility that glucose loading was injurious to cells, 3H-leucine uptake (as a measure of protein synthesis) and membrane alkaline phosphatase activity (as a biochemical marker of viability) were not affected by the high glucose condition.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Decreased degradative enzymes in mesangial cells cultured in high glucose media. 762 99

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

Vascular endothelial growth factor (VEGF) is a dimeric glycoprotein that exerts a proliferative effect specifically on endothelial cells. VEGF can increase vascular permeability and collagenase activity, is chemotactic for monocytes, and may dilate blood vessels. It can be induced by phorbol ester and cAMP in both mesenchymal and epithelial cells. In vitro cell culture experiments suggest that VEGF is upregulated by oxygen deprivation. In this study we tested whether in vivo acute and/or chronic reduction of renal blood flow by vascular obstruction would result in increased expression of VEGF mRNA and protein. Three normal kidneys, five human kidneys with narrowing of preglomerular vessels by vascular rejection or by vasculitis, and eight kidneys with nephrosclerosis and/or diabetic nephropathy were examined. In situ hybridization with 35S-labelled riboprobes showed a pronounced expression of VEGF mRNA in acutely hypoxic proximal and distal tubules of both the cortex and medulla; VEGF protein was demonstrated in the epithelia of these tubules by immunohistochemistry. In kidneys with chronically reduced blood flow, the majority of atrophic tubules were negative for VEGF mRNA and protein, although interstitial cells expressed VEGF mRNA. In arcuate arteries showing intimal and adventitial fibrosis, some medial smooth muscle cells were positive for VEGF mRNA. In glomeruli with segmental sclerosis, viable podocytes showed a prominent signal for VEGF mRNA. Mesangial cells did not express VEGF in the cases studied. It is possible that hypoxia itself led to the upregulation of VEGF in tubular epithelia and vascular smooth muscle cells. The vasodilatory and permeability-promoting effects of the endothelial growth factor produced by damaged tubular epithelia may constitute a mechanism to alleviate a decrease in blood flow and substrate availability and to re-establish vascular integrity.
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PMID:Expression of vascular endothelial growth factor in renal vascular disease and renal allografts. 855 88

We evaluated the role of tissue inhibitors of metalloproteinase-1 (TIMP-1) in patients with diabetic nephropathy by comparing the serum and urine TIMP-1 levels with those of renal biopsy specimens. A total of 35 diabetic patients were divided into four groups, D0, DI, DII and DIII-IV, according to the severity of diffuse glomerular lesions using Gellman's criteria. Using serum and 24-hour urine specimens, TIMP-1 was measured by a sandwich enzyme immunoassay. Serum and urinary TIMP-1 showed significant increases in association with the progress of glomerular diffuse lesions. There was no correlation between serum TIMP-1 and serum creatinine, creatinine clearance, serum and urinary beta 2-microglobulin, urinary NAG, HbA1c, or urinary TIMP-1. There was a significant correlation between urinary TIMP-1 and urinary albumin, and was a significant correlation between urinary TIMP-1 and urinary NAG. We conclude that TIMP-1 has a potential role in the regulation of glomerular matrix accumulation in diabetic nephropathy.
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PMID:Role of tissue inhibitors of metalloproteinase in diabetic nephropathy. 872 33

Mesangial cells are responsible for the synthesis of mesangial matrix as well as its degradation, which is mediated by a number of proteolytic activities, including metalloproteinases (MMPs). Imbalanced matrix protein metabolism may be responsible for mesangial expansion and glomerulosclerosis in diabetic nephropathy. Heparin prevents this complication. In human and murine mesangial cell cultures, RT-PCR was able to detect mRNA expression for a number of molecules involved in the mesangial extracellular matrix turnover: type IV collagen [alpha 1(IV)COLL], MMP-1, MMP-2, MMP-3, MMP-9 and MMP-10, and the tissue inhibitors TIMP-1 and TIMP-2. The expression of mRNA for alpha 1(IV)COLL and MMP-2/TIMP-2 balance was studied in human cells in the presence of high glucose and heparin. mRNAs for all the studied molecules were expressed at different levels. Interestingly, a shift in the balance of alpha 1(IV)COLL, MMP-2 and TIMP-2 was observed in high glucose, which was partially reversed by heparin supplementation. The new equilibrium was mostly due to the down-regulation of type IV collagen expression, rather than further reduction of potential proteolysis. Our data, while extending the list of potential mediators of mesangial matrix catabolism, highlight a molecular mechanism by which the pathogenesis of diabetic nephropathy may be sustained, and at the same time suggest that heparin may have the potential to correct this abnormality.
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PMID:Effect of glucose and heparin on mesangial alpha 1(IV)COLL and MMP-2/TIMP-2 mRNA expression. 907 22

Progressive expansion of the mesangial matrix is one of the most characteristic histological features of diabetic nephropathy (DN). To determine the balance between the turnover and degradation of extracellular matrix (ECM) in renal tissue of patients with DN, we examined the expression of matrix metalloproteinase-3 (MMP-3), tissue inhibitor of metalloproteinase-1 (TIMP-1) and type IV collagen (IV-C) mRNAs using a high-resolution in situ hybridization. Patients were divided into three grades: mild (grade I), moderate (grade II) and severe (grade III) mesangial expansion and tubulointerstitial injury. The relationship between the expression of these mRNAs and degree of glomerular mesangial expansion and interstitial injury was also examined. Cells positive for each mRNA were observed in glomerular resident cells, including glomerular mesangial, epithelial and endothelial cells and cells of Bowman's capsule. A number of tubular epithelial cells and some infiltrating cells in the interstitium also expressed these mRNAs. The expression of MMP-3 mRNA and TIMP-1 mRNA was strongest in glomeruli of grade I and inversely correlated with mesangial expansion. In contrast, the expression of all three types of mRNA was correlated with the degree of interstitial injury. Our results indicate that IV-C, MMP-3 and TIMP-1 mRNAs are expressed in glomerular resident cells, tubular epithelial cells and infiltrating cells in renal tissue of DN, and suggest that their expression changes with the degree of mesangial expansion and interstitial injury. Altered expression of MMP-3 and TIMP-1 may be associated with the progression of DN.
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PMID:In situ hybridization studies of matrix metalloproteinase-3, tissue inhibitor of metalloproteinase-1 and type IV collagen in diabetic nephropathy. 921 53

Excessive production and deposition of extracellular matrix proteins are characteristic features of diabetic nephropathy. This study tests the hypothesis that cells from diabetic patients who develop nephropathy have a disturbance in collagen metabolism compared with cells from diabetic patients without complications. Kinetics of overall collagen metabolism and total protein synthesis were examined in serially passaged, subconfluent, quiescent skin fibroblasts cultured in either normal (5 mM) or high (25 mM) glucose concentrations from 14 insulin-dependent diabetic (IDDM) patients with nephropathy; 14 IDDM patients without nephropathy matched for age, diabetes duration, and body mass index; and 14 healthy subjects. Fibroblasts were incubated in the presence of 2 microCi/ml [3H]proline, and after labeling the incorporation of [3H]proline into total protein, collagen (collagenase-sensitive material), and noncollagen proteins (collagenase-resistant material) was determined at different time points. Collagen degradation was determined in pulse-chase experiments by following the residual collagen-bound radioactivity after incubation for 8 h with 10 microCi/ml [3H]proline. In high glucose concentrations (25 mM), overall collagen synthesis (measured as [3H]proline incorporation into extracellular and intracellular collagenase-sensitive material) was significantly greater in the patients with nephropathy (mean +/- SEM after a 24-h labeling period: 7189 +/- 671 dpm/10(6) cells) than in the patients without (4341 +/- 267 dpm/10(6) cells; P < 0.01) or healthy control subjects (3836 +/- 234 dpm/10(6) cells; P < 0.01). No significant differences were observed in noncollagen protein production or in collagen degradation rates among the three groups of subjects. In the presence of normal glucose concentrations (5 mM), collagen synthesis was lower in all groups studied, but the differences between IDDM patients with nephropathy and those without remained unaltered. These results suggest that long-term cultured fibroblasts derived from diabetic patients with nephropathy exhibit an abnormality in collagen metabolism. Cells from long-standing diabetic patients without nephropathy have normal collagen metabolism. The increased collagen synthesis is likely to be intrinsic to those diabetic patients susceptible to nephropathy and may play an important role in the sclerotic processes that occur in the kidneys, arteries, and heart.
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PMID:Enhanced collagen synthesis in cultured skin fibroblasts from insulin-dependent diabetic patients with nephropathy. 921 63

Glomerulosclerosis and tubulointerstitial fibrosis are common morphological correlates of many end-stage kidneys. There is ample evidence that transforming growth factor-beta (TGF-beta) plays a major role in these alterations by directly stimulating synthesis of many extracellular matrix components and reducing collagenase production, finally leading to renal scarring. Although many factors may induce TGF-beta expression in the kidney, one very interesting aspect is the link between angiotensin II (ANG II) and TGF-beta. Originating from observations in vascular smooth muscle cells, there are now several additional studies showing that ANG II stimulates TGF-beta expression in the kidney. Although cell culture studies have convincingly demonstrated that the vasoactive peptide directly stimulates transcription as well as bioactivation of TGF-beta, the in vivo evidence is more indirect. Nevertheless, there are several pathophysiological situations including unilateral ureteral obstruction, chronic cyclosporin A nephrotoxicity, various models of hypertension, and probably diabetic nephropathy in which ANG II-mediated TGF-beta induction has been demonstrated to play an important role in the progression of the disease. The fascinating aspect of this relationship between ANG II and TGF-beta is the fact that hemodynamic changes as well as structural changes are linked together generating a unifying model of progression of chronic renal failure with ANG II as the key player. Angiotensin-converting enzyme (ACE) inhibitor and the more recently introduced AT1-receptor blocker may be potential drugs to interfere with this ANG II-mediated TGF-beta expression. Therefore, these drugs should not only be considered as antihypertensive medications, but should rather be viewed as renoprotective substances influencing renal remodeling by preventing local TGF-beta expression.
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PMID:Link between angiotensin II and TGF-beta in the kidney. 952 2

In this study, cultured glomerular epithelial cells (GEC) were exposed to a diabetic milieu containing glycated proteins to determine whether such proteins cause metabolic alterations that may lead to defects seen in the extracellular matrix in diabetic nephropathy. Cultured glomerular epithelial cells were cloned and maintained in RPMI media containing 10% fetal bovine serum (FBS). The medium was changed to RPMI-1% glycated FBS (experimental) or RPMI-1% control FBS, and cells were incubated for 1 or 4 d. Mitogenicity was tested by 3H-thymidine uptake. The media were collected and analyzed for collagenase activity by a quantitative fluorescence assay and by zymography. The cell layers were processed for matrix antigen (collagen I, glomerular basement membrane antigens, laminin, and fibronectin) and for the proteins of the tight junction (cadherin, desmosomal protein) by quantitative immunoperoxidase and immunofluorescence. Cell lysates were tested for cadherin and desmosomal protein by immunoblotting. Cells were also grown on 0.2-microM filter membranes to test for permeability to 3H-inulin and 125I-albumin. Glycated FBS resulted in a 1.8-fold increase in 3H-thymidine uptake in subconfluent layers accompanied by an increase in cell number. The treatment caused accumulation of laminin (18% above control, P < 0.05) and basement membrane antigens (33% above control, P < 0.05). Collagen I and fibronectin were unchanged. Exposing cells to glycated FBS changed the distribution of cadherin from a linear to a diffuse pattern associated with a decrease in cadherin observed on immunoblots. The media of glycated FBS-treated cells contained 45% lower collagenase activity (72-, 92-, and 150-kD species). Permeability to inulin increased by 550% and to albumin by 320% in glycated FBS-treated monolayers compared with controls. It is concluded that glycated proteins increased the accumulation of matrix proteins in the GEC, associated with a concomitant depression in collagenase activity. There were qualitative and quantitative changes in the tight junction protein cadherin. These matrix changes resulted in a functional defect in the permselective properties of the GEC tight junctions and manifested as increased leakage of inulin and albumin. Thus, the GEC are metabolically sensitive to the presence of glycated proteins, and this could play a role in the pathogenesis of diabetic nephropathy.
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PMID:Effect of glycated proteins on the matrix of glomerular epithelial cells. 959 77

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