Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011881 (diabetic nephropathy)
 10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous investigations have demonstrated that growing mesangial cells in high glucose concentration stimulates extracellular matrix synthesis and also increases the expression of TGF-beta. We tested whether the stimulation of extracellular matrix production is mediated by autocrine activation of TGF-beta, a known prosclerotic cytokine. Addition of neutralizing anti-TGF-beta antibody, but not normal rabbit IgG, significantly reduced the high glucose-stimulated incorporation of 3[H]proline. Denaturing SDS-PAGE revealed that mainly collagen types I and IV were stimulated by high (450 mg/dl) D-glucose. This high glucose-mediated increase in collagen synthesis was reduced by the anti-TGF-beta antibody. Treatment of mesangial cells grown in normal (100 mg/dl) D-glucose with 2 ng/ml recombinant TGF-beta 1 mimicked the effects of high glucose. Furthermore, the anti-TGF-beta antibody significantly reduced the increase in mRNA levels encoding alpha 2(I) and alpha 1(IV) collagens induced by high glucose. Thus, the high glucose-stimulated increase of collagen production in mesangial cells is mediated, at least in part, by autocrine TGF-beta activation. We postulate that the interception of the glomerular activity of TGF-beta may be an effective intervention in the management of diabetic nephropathy.
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PMID:Stimulation of collagen gene expression and protein synthesis in murine mesangial cells by high glucose is mediated by autocrine activation of transforming growth factor-beta. 811 92

High glucose and elevated levels of advanced glycosylation end products (AGEs) exert an antiproliferative effect on cultured mesangial cells. In view of the role of oxygen free radicals in the pathogenesis of diabetic nephropathy, we tested whether two endogenous antioxidants, taurine and vitamin E, ameliorate the effects of an elevated ambient glucose and/or AGEs on mesangial cell growth in vitro. Regardless of whether cell proliferation was assayed by the incorporation of [3H]thymidine, direct cell counting or bromodeoxyuridine (BrdU) cell staining, both taurine and vitamin E reversed the inhibitory effect of high glucose and AGEs on mesangial cell growth. In conjunction with our previous studies indicating that taurine and vitamin E reduce collagen production in mesangial cells exposed to high glucose, these findings suggest that endogenous antioxidants attenuate diabetic glomerulosclerosis by interfering with the bioactivation of transforming growth factor-6.
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PMID:Antioxidants reverse the antiproliferative effect of high glucose and advanced glycosylation end products in cultured rat mesangial cells. 812 33

Diabetic serum contains increased concentrations of glycated proteins, which are preferentially transported into the renal glomerulus. We investigated effects of Amadori glucose adducts in serum proteins, the predominant form in which circulating glycated proteins exist in vivo, on glomerular mesangial cells, where the lesion of diabetic nephropathy originates. [3H]-thymidine incorporation by murine mesangial cells was significantly inhibited when cells were grown in the presence of serum glycated by incubation for four days with 28 mM glucose or when cells were cultured in microtiter plates that had been precoated with glycated serum. This effect was prevented by a monoclonal antibody immunoreactive with Amadori adducts in glycated albumin, and unreactive with other glycated serum proteins or with advanced glycation end (AGE) products. Glycated serum stimulated Type IV collagen gene expression and increased Type IV collagen secretion, an effect also prevented by monoclonal antibodies reactive with Amadori adducts in glycated albumin. The glycation-induced changes in proliferation, collagen synthesis and collagen gene expression were observed in media containing normal glucose concentration and were exaggerated in media containing high glucose concentration. The data indicate that Amadori products of glycated serum proteins induce mesangial cell abnormalities that are highly relevant to the pathogenesis of diabetic nephropathy, and that these effects are accentuated when glycated serum proteins are presented in a hyperglycemic milieu. The data also suggest that mesangial cells specifically recognize Amadori adducts in glycated albumin.
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PMID:Amadori glucose adducts modulate mesangial cell growth and collagen gene expression. 816 36

Diabetic nephropathy is characterized by albuminuria which proceeds to overt proteinuria. The highly negatively stained HS side chain of heparan sulphate proteoglycan (HSPG) is a major determinant of the charge-dependent permeability of the GBM. We set out to study the presence of HS and HSPG in the GBM of patients with diabetic nephropathy using newly developed monoclonal antibodies, and to compare HSPG expression to the expression of other previously investigated glomerular extracellular matrix compounds. Immunohistochemically, glomerular extracellular matrix components were analysed in 14 renal biopsies of patients with diabetic nephropathy and compared with those of normal control subjects. Monoclonal antibodies used were: JM403 against the HS side chain of GBM HSPG and JM72 against the HSPG-core protein. Also, a polyclonal antiserum (B31) against human GBM-HSPG-core protein was used. Additionally, antibodies were used against collagen types I, III, IV and against alpha 1 (IV)NC, alpha 3(IV)NC and fibronectin. Staining was scored for intensity and for staining pattern by four independent observers who had no previous knowledge of the sample origin. No glomerular staining was seen for collagen type I. Collagen type III was present in some diabetic nodules. Anti-collagen type IV showed a decreased GBM staining in patients with diabetic nephropathy (p = 0.04). With anti-alpha 1 (IV)NC no changes in GBM staining intensity were observed; with anti-alpha 3 (IV)NC brilliant GBM staining was seen in both groups. Increased mesangial staining (p = 0.003) was seen with anti-collagen type IV in biopsies with nodular lesions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression of glomerular extracellular matrix components in human diabetic nephropathy: decrease of heparan sulphate in the glomerular basement membrane. 748 52

Glomerular basement membrane thickening and mesangial expansion are the main pathological features in diabetic nephropathy--glomerulosclerosis with the biochemical correlate of increased collagen accumulation. We studied a new principle to reduce collagen accumulation in the glomerulus: thiaproline, known to inhibit protein synthesis by blocking the elongation, led in our studies to a morphological reduction of the glomerular basement membrane thickening and to a decreased collagen content. As the thiaproline analogue is incorporated into collagen, the mechanism of increased degradation of the modified collagen is being discussed.
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PMID:Thiaproline reduces glomerular basement membrane thickness and collagen accumulation in the db/db mouse. 819 Jan 87

Nonenzymatically glycated proteins are preferentially transported across the glomerular filtration barrier, and the glomerular mesangium in diabetes is bathed with serum containing increased concentrations of glycated albumin. We investigated effects of glycated albumin on mesangial cells, which are involved in diabetic nephropathy. [3H]-thymidine incorporation was significantly inhibited when murine mesangial cells were grown in culture media containing human serum that had been nonenzymatically glycated by incubation for 4 days with 28 mM glucose. This inhibition was reversed when monoclonal antibodies that selectively react with Amadori products of glycated albumin were added to the culture media. Purified glycated albumin containing Amadori adducts of the glycation reaction induced significant inhibition of thymidine incorporation and stimulation of Type IV collagen secretion compared with cells cultured in the presence of purified nonglycated albumin. These changes were prevented when monoclonal antibodies specifically reactive with fructosyl-lysine epitopes in glycated albumin were added to the cultures. The antibodies had no effect on growth or collagen production in the presence of nonglycated albumin. The results provide the first evidence directly implicating Amadori adducts in glycated albumin in the pathogenesis of diabetic nephropathy, which is characterized by decreased cellularity in association with expansion of the mesangial matrix.
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PMID:Effects of glycated albumin on mesangial cells: evidence for a role in diabetic nephropathy. 826 68

We attempted to reevaluate the clinical significance of two parameters, 1,5-anhydroglucitol (AG) and type IV collagen, which are widely available in the fields of clinical activity. 1) 1,5 AG 1,5 AG was measured as a marker of glycemic control for diabetic patients by means of a column-enzymatic test (Nippon Kayaku Co., Ltd). Serum 1, 5 AG levels in diabetic patients (3.0 +/- 5.8 micrograms/ml, mean +/- SD) were significantly lower than in normal subjects (22.4 +/- 6.9 micrograms/ml). 75 g OGTT was performed on 428 subjects with urinary glucose detected on previous medical examination. According to the selectivity index (sensitivity value x specificity value) and the receiver operating characteristic curve (ROC) for diabetes, glycosylated hemoglobin (HbA1c) was slightly superior to 1,5 AG and fructosamine for diabetes screening. Furthermore, unexpectedly high levels of 1, 5 AG were obtained from the plasma of diabetic patients with this kit, when the patients were given a drip infusion containing maltose. We found that the maltose contained in the assay system interfered with measurement of 1, 5 AG. Nevertheless, 1, 5 AG measurements are thought to be useful in the diagnosis and screening of diabetes mellitus because of its wideranging fluctuations under relatively good glycemic control, as suggested by Yamanouchi, et al. 2) type IV collagen The type IV collagen peptide is known as a useful marker of progressive liver diseases and early stages of diabetic nephropathy. Type IV collagen was measured by one step sandwich enzyme immunoassay (EIA) using monoclonal antibodies (Panaassay IV CL; Fuji Chem. Ind., Ltd).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Clinical markers in endocrine-metabolic diseases]. 835 14

The development of proliferative retinopathy in type 2 diabetes mellitus may be under genetic control. A well-documented pathological change in the fundal capillaries of patients with diabetic retinopathy is basement membrane thickening, with an increased amount of collagen IV protein. Variation at the collagen 1a IV gene therefore may explain familial susceptibility to this complication. It has been previously reported that genetic variation at the collagen 1a locus, as shown by allelic association with a HindIII restriction site, predisposes to diabetic nephropathy where basement membrane thickening is also prevalent. In order to test the hypothesis that the collagen 1a IV gene locus is important in the development of diabetic retinopathy, a population association study was performed comparing allele frequencies of the HindIII RFLP in diabetic patients with retinopathy and controls. No statistically significant differences were found between allele frequencies or genotypes in the two groups. The future use of similar studies in diabetic retinopathy is discussed.
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PMID:Genetic variation around the collagen IV 1a gene locus and proliferative retinopathy in type 2 diabetes mellitus. 835 15

Like the renal glomerular mesangium in patients with diabetic nephropathy, glomerular mesangial cell cultures grown in 30 mM glucose accumulate increased amounts of the extracellular matrix (ECM) proteins fibronectin, laminin, and type IV collagen. This is due to increased ECM protein synthesis and mRNA levels. Similar to other cells types that are affected by the diabetic state (such as, vascular cells and peripheral nerve), mesangial cells transport glucose by an insulin-independent, facilitated diffusion transport system. Kinetic studies reveal that intracellular glucose levels may reach the ambient glucose concentrations achieved in diabetes. Growth studies reveal that glucose does not exert its effect on mesangial cell ECM accumulation by affecting cell growth, but rather it causes an increase in diacylglycerol (DAG) mass and activates protein kinase C. Agents such as phorbol myristate acetate (PMA) and the cell permeable DAG analogue, oleoyl acetyl glycerol (OAG) which activate protein kinase C also increase ECM mRNAs. These results implicate protein kinase C activation in the increased ECM accumulation observed in mesangial cell cultures grown in high glucose.
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PMID:The glomerular mesangium in diabetes mellitus. 843 49

The pathogenesis of the multiple structural lesions in diabetic nephropathy remains debated, and likely is multifactorial. The uniform thickening of the renal basement membranes lining the glomerular and tubular elements appears to be a consequence of the metabolic perturbations which are directly related to hyperglycemia. While most investigations have focused on the increased accumulation of extracellular matrix in the glomerular basement membrane and the mesangium, and their relation to derangements in glomerular function, little is known regarding the pathogenesis and the significance of the tubulointerstitial changes and the thickened tubular basement membrane (TBM). It is possible that these latter changes are causally related to the cellular hypertrophy of the renal tubular epithelium that lines the TBM. It has been postulated that in the earlier stages of the disease, hyperglycemia induces renal tubular hypertrophy and stimulates the synthesis of the various matrix components which are normal constituents of the TBM. Later, the structural composition of the TBM is susceptible to further modifications by non-enzymatic glycation, and this aberrant process may impart a relative resistance to matrix degradation leading to a slow turnover. In vitro investigations on murine proximal tubule cells in culture have provided evidence that elevated ambient glucose is a sufficient stimulus for cellular hypertrophy and increased biosynthesis of collagen type IV, the predominant constituent of TBM. High glucose levels increase steady-state collagen IV mRNA, partly due to transcriptional activation of cis-acting elements of the gene which are controlled by putative glucose-responsive trans-acting proteins.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Renal tubular basement membrane and collagen type IV in diabetes mellitus. 843 50


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