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)

To elucidate the characteristics of glycoproteins in the mesangial matrix in glomeruli from patients with diabetic nephropathy (DN) in non-insulin-dependent diabetes mellitus (NIDDM), we examined periodic acid-Shiff (PAS) and immunofluorescence staining of types III (III-C), IV (IV-C), V (V-C) and VI (VI-C) collagen, fibronectin (FN), fibrinogen (FBG) and laminin (LN) in the glomeruli of 16 patients with DN and 12 patients with diffuse proliferative glomerulonephritis (DPGN). The percentage of positively staining areas in the glomeruli were calculated using an automatic image analyzer. The percentages of areas positive for PAS, III-C, IV-C, V-C, VI-C or FN in DN were significantly greater than those in DPGN. Moreover, the percentages of PAS-positive areas were significantly correlated with not only IV-C-positive areas, but also FN-positive areas in patients with DN. The percentages of PAS-positive areas were also significantly correlated with the levels of serum creatinine and the degree of proteinuria in these patients. It was concluded that mesangial expansion in this disease might be associated mainly with an increase in IV-C and FN. These changes appear to affect the deterioration of renal function and the appearance of proteinuria, and vice versa.
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PMID:Measurement of the extracellular matrix in glomeruli from patients with diabetic nephropathy using an automatic image analyzer. 785 51

Detection of glycosylated protein in renal tissues was determined in streptozotocin (STZ)-induced diabetic rats using the nitroblue tetrazolium (NBT) reaction. The glycosylation of extra-cellular matrix (ECM) components such as laminin and fibronectin was examined in vitro using the same method. Immunofluorescence staining of laminin or type IV collagen was also performed in renal tissues of STZ-induced diabetic rats. There was no significant difference in the intensity of NBT in renal tissues between 4 week STZ-induced diabetic rats and control rats of the same age. The intensity of NBT staining in the glomerular mesangial areas and capillary walls was marked in 12 week diabetic rats. The mean values of fructosamine measured by the NBT reaction in the glycosylated-laminin and fibronectin were increased dose dependently. In immunofluorescence, laminin and type IV collagen were observed significantly in the glomerular mesangial areas and capillary walls of 12 week diabetic rats. However, there was no significant change in renal histopathology in 4 and 12 weeks diabetic rats. It appears that the non-enzymatic glycosylation and expression of ECM components in glomeruli increased in the early stage of diabetic nephropathy prior to the appearance of marked histologic alterations. In conclusion, non-enzymatic glycosylation of glomerular structural components may play an important role in the initiation of the early stage of renal injuries in diabetes.
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PMID:Detection of glycosylated protein in glomeruli of STZ-induced diabetic rats using the nitroblue tetrazolium (NBT) reaction. 793 13

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

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

To explore the possibility that the excretion of urinary fibronectin degradation products (U-FnDP) can be an indicator of the progression of diabetic nephropathy, U-FnDP and urinary protein(U-P) were determined in 64 diabetic patients and 11 healthy volunteers. Moreover, to determine whether continuous subcutaneous heparin infusion (CSHI) reduces elevated U-FnDP and U-P in diabetic patients with persistent proteinuria, heparin sodium was administered as a bolus subcutaneous injection of 5000 IU, followed by subcutaneous infusion of 250 IU/kg per 24 h heparin sodium for 7 days. U-FnDP excretion rate elevated proportionally to the degree of U-P. CSHI reduced significantly elevated U-FnDP from 172.68 +/- 15.79 to 100.04 +/- 14.93 micrograms/24 h (P < 0.01) and U-P from 1.76 +/- 0.13 to 1.20 +/- 0.12 g/24 h (P < 0.01). No significant changes in blood pressure and diurnal mean plasma glucose levels were found. APTT was prolonged with a decrease of AT-III activity during the treatment. These findings suggest that U-FnDP can be one of the indicators which reflects the degree of progression of diabetic nephropathy, and that CSHI may be useful for the normalization of elevated U-FnDP and reduction in U-P in diabetic nephropathy.
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PMID:Relationship between urinary excretion of fibronectin degradation products and proteinuria in diabetic patients, and their suppression after continuous subcutaneous heparin infusion. 825 24

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

Diabetic nephropathy is characterized by renal hypertrophy, thickening of basement membranes, and accumulation of extracellular matrix in the glomerular mesangium and the interstitium. Our previous investigations have shown that high glucose concentration increases transforming growth factor (TGF)-beta1 mRNA in mesangial and proximal tubule cells and that treatment with anti-TGF-beta antibody results in prevention of the effects of high glucose on cell growth (e.g., induction of cellular hypertrophy) and the stimulation of collagen biosynthesis. We evaluated in vivo the functional role of the renal TGF-beta system in diabetic kidney disease by treatment of streptozotocin-induced diabetic mice with either a neutralizing monoclonal antibody against TGF-beta1, -beta2, and -beta3 (alphaT) or nonimmune murine IgG for 9 days. Diabetic mice given IgG demonstrated total kidney and glomerular hypertrophy, significantly elevated urinary TGF-beta1 protein, and increased mRNAs encoding TGF-beta1, type II TGF-beta receptor, alpha1(IV) collagen, and fibronectin. Treatment of diabetic mice with alphaT prevented glomerular hypertrophy, reduced the increment in kidney weight by approximately 50%, and significantly attenuated the increase in mRNA levels without having any effect on blood glucose. The antibody was without significant effect on mRNA levels in nondiabetic mice. This is the first demonstration that the early characteristic features of diabetic renal involvement, which include hypertrophy and increased matrix mRNAs, are largely mediated by increased endogenous TGF-beta activity in the kidney and that they can be significantly attenuated by treatment with neutralizing anti-TGF-beta antibodies.
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PMID:Neutralization of TGF-beta by anti-TGF-beta antibody attenuates kidney hypertrophy and the enhanced extracellular matrix gene expression in STZ-induced diabetic mice. 860 76

We recently reported that when diabetic db/db mice, which develop glomerular pathology resembling that in human diabetes mellitus, are treated with monoclonal antibodies (A717) that neutralize the effects of excess glycated albumin, there is an amelioration of mesangial expansion, renal overexpression of mRNAs encoding for the extracellular matrix proteins collagen IV and fibronectin and proteinuria. These findings suggested that A717 might also retard the development of compromised renal function in this animal model. To examine this possibility, serum creatinine and blood urea nitrogen (BUN) were measured in diabetic db/db mice and their non-diabetic db/m littermates before and after an 8-week course of treatment with A717 or irrelevant murine immunoglobulin (MIg). Early in the course of diabetes, BUN and serum creatinine concentrations did not significantly differ from those in the db/m littermates, but were significantly increased after 10 weeks of sustained hyperglycaemia. Treatment of db/db mice with A717 prevented the rise in creatinine and attenuated the elevation in BUN. A717 also prevented the decrease in creatinine clearance observed in diabetic compared with non-diabetic animals (2.2 +/- 0.8 vs 4.1 +/- 0.3 vs 5.0 +/- 1.1 ml/h in db/db vs db/db-A717 vs db/m, respectively). MIg did not alter the change in renal function with time in db/db mice. Taken together with our previous results, the present findings indicate that the diabetic db/db mouse develops changes in renal function and structure that parallel the course of human diabetic nephropathy in nature and chronology and demonstrate, for the first time, that therapy directed against increased glycated albumin can prevent the decline in renal function in this rodent model of genetic diabetes.
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PMID:Prevention of decline in renal function in the diabetic db/db mouse. 872 71

Accelerated nonenzymatic glycation in diabetes, resulting in Amadori-modified proteins and the later-developing advanced glycation end-products, has been mechanistically linked to the pathogenesis of diabetic nephropathy. Recent focus on putative AGE-induced pathophysiology has shifted attention from the possible role of Amadori-modified proteins in the development of diabetic complications. Ample experimental evidence has demonstrated that Amadori-modified serum proteins adversely affect renal glomerular capillary function, structure, and metabolism. Previous studies from the laboratories of this study's authors have shown that human serum containing diabetic concentrations of albumin modified by Amadori-glucose adducts inhibits the replication of murine mesangial cells in culture and stimulates the production and gene expression of type IV collagen. Monoclonal antibodies (A717) specific for Amadori-glycated albumin prevent these abnormalities. In other studies, it has also been shown that in vivo administration of A717 (Fab fragments) retards the progression of diabetic nephropathy in diabetic db/db mice. Neutralizing the effects of the elevated circulating glycated albumin concentration is associated with reduction in proteinuria and mesangial matrix expansion, and prevention of the overexpression of mRNA encoding type IV collagen and fibronectin in the renal cortex. The renoprotective effects of A717 are independent of any change in blood glucose concentrations. These studies implicate Amadori-modified glycated albumin in the pathogenesis of diabetic nephropathy. It is proposed in this study that abrogating the biologic effects of increased glycated albumin in diabetes has novel therapeutic potential in the management of diabetic renal complications.
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PMID:Role of Amadori-modified nonenzymatically glycated serum proteins in the pathogenesis of diabetic nephropathy. 878 86

Protein and mRNA expression of TGF-beta isoforms, TGF-beta 1, -beta 2 and -beta 3, and deposition of fibronectin containing extra domain A (fibronectin EDA+) and plasminogen activator inhibitor-1 (PAI-1) were studied in human chronic glomerulonephritis and diabetic nephropathy. Normal kidneys showed similar, weak immunostaining for all three TGF-beta isoforms. TGF-beta mRNA expression was weak for all isoforms with TGF-beta 1 > TGF-beta 3 >> TGF-beta 2. In thin basement membrane disease and minimal change disease, disorders where extracellular matrix accumulation is not a feature, immunoreactivity and mRNA expression did not differ from normal. In contrast, diseases characterized by extracellular matrix accumulation (IgA nephropathy, focal and segmental glomerulosclerosis, crescentic glomerulonephritis, lupus nephritis and diabetic nephropathy) all showed significantly increased expression of the three TGF-beta isoforms in glomeruli and the tubulointerstitium. While glomerular and tubulointerstitial deposition of two matrix components induced by TGF-beta, fibronectin EDA+ and PAI-1, was significantly elevated in all diseases with matrix accumulation, correlation analysis revealed a close relationship primarily with TGF-beta 1. We conclude that, for a spectrum of human glomerular disorders, increased protein expression of all three TGF-beta isoforms and proteins induced by TGF-beta is associated with pathological accumulation of extracellular matrix.
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PMID:Expression of transforming growth factor-beta isoforms in human glomerular diseases. 882 30

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