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)

Limited joint mobility seen in diabetes mellitus is thought to be the result of stiffening of periarticular connective tissue, which is presumably derived from increased cross-linking of collagen related to advanced glycation end products. In this study the extent of the stiffening of connective tissue was measured by the passive extension angle of the metacarpophalangeal joints in 205 elderly diabetic patients. Association with diabetic nephropathy, with which advanced glycation end products have recently been demonstrated to increase, and metabolic abnormalities were also considered. The angle of the metacarpophalangeal joints was significantly correlated with age (r = -0.24, p < 0.01), and was significantly smaller in men than in women (p < 0.01). The angle demonstrated a decrease in association with diabetic retinopathy and nephropathy, and only the association with nephropathy was significant (p < 0.05). The angle was weakly, but significantly, correlated with serum thiobarbituric acid reactants as a measure of lipid peroxides (r = -0.15, p < 0.05), triglyceride (r = -0.20, p < 0.01) and HDL cholesterol (r = 0.19, p < 0.01), but not with blood glucose (r = 0.02), HbA1c (r = 0.06) or duration of diabetes (r = -0.05). In addition, the angle in 14 non-diabetic patients on haemodialysis was significantly (p < 0.05) smaller than that in age- and sex-matched normal subjects. Thus, it was indicated that the stiffening of connective tissue was associated with diabetic nephropathy, serum lipid peroxide and dyslipidaemia. Stiffening of connective tissue seems to be more affected by oxidative stress than non-enzymatic glycation per se.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Stiffening of connective tissue in elderly diabetic patients: relevance to diabetic nephropathy and oxidative stress. 843 58

Hyperglycemia is directly involved in the development of diabetic nephropathy. A high glucose concentration promotes membrane lipid peroxidation and stimulates collagen production in a variety of cultured cells. Taurine, a sulfur amino acid, is an endogenous antioxidant and antifibrotic agent. We tested whether taurine ameliorates the above effects of elevated ambient glucose on renal cells in vitro. Raising glucose concentration from 5.6 to 33.3 mM enhanced lipid peroxidation in rat mesangial cells, as assessed by malondialdehyde and conjugated diene content, and increased collagen production by 59%. Taurine prevented both glucose-induced effects in mesangial cells. In contrast, neither high glucose nor taurine, alone or in combination, affected lipid peroxidation or collagen production in MDCK or LLC-PK1 cells, derived from renal tubular epithelium. These results indicate that taurine may be a useful therapeutic agent to attenuate diabetic glomerulosclerosis.
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PMID:Taurine prevents glucose-induced lipid peroxidation and increased collagen production in cultured rat mesangial cells. 846 Oct 28

Diabetic late complications are characterized by morphological and biochemical alterations of the extracellular matrix. In particular, longstanding diabetes causes quantitative and qualitative changes in basement membrane structure of retinal and renal capillaries. Immunohistochemical investigations of diabetic kidneys with diffuse glomerulosclerosis show increased collagen type IV deposition in the mesangial matrix and decreased heparan sulfate proteoglycan content in the mesangial matrix and glomerular basement membrane as well. In nodular glomerulosclerosis normal basement membrane components are decreased or absent while the occurrence of collagen type III in this stage has been interpreted as an irreversible alteration of the glomerular structure. These changes seem to be the underlying cause for the alterations in renal functions like persistent albuminuria and proteinuria. Increased intra- and extracellular levels of glucose and its derivatives are thought to be responsible for diabetic tissue dysfunction although there are reports on possible genetic defects causing increased susceptibility to develop diabetic nephropathy. Recent results, however, focus on the role of glucose-induced cytokine secretion as mediator for altered metabolism of glomerular matrix proteins. In vitro studies with cultured kidney cells have shown that the glucose-induced dysregulation of the basement membrane synthesis may be mediated by a glucose dependent activation of protein kinase C. Alternatively or synergistically, the formation of AGE products formed after prolonged exposure of matrix proteins to elevated glucose may also lead to cytokine secretion subsequently inducing synthesis of extracellular matrix proteins. Studies in experimental animals confirm the diabetes induced dysregulation of the synthesis of extracellular matrix components on the molecular level.
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PMID:Alterations of glomerular matrix proteins in the pathogenesis of diabetic nephropathy. 851 35

Accelerated atherosclerosis is commonly observed in diabetes mellitus as well as in some kidney diseases. This may be partly due to platelet hyperactivity. Serotonin (5-HT) is thought to play a role in platelet/vessel wall interactions and to be implicated in the pathogenesis of atherosclerosis. The aim of the study was to evaluate platelet aggregation and peripheral serotonergic system in patients with diabetic nephropathy. The studies were performed in 37 patients with diabetic nephropathy (age 53.5 +/- 14.9) and healthy volunteers (age 44.2 +/- 12.3). Platelet aggregation (in PRP according to Born) induced by collagen (2 micrograms/ml), ADP (5 microM), epinephrine (10 microM) arachidonic acid (0.25 mM) and 5-HT (1 microM) was found to be significantly enhanced in diabetic relative to controls. Whole blood 5-HT was significantly lower in diabetics patients, whereas plasma 5-HT was significantly higher in diabetic patients when compared to controls. Since serotonin can amplify platelet aggregatory responses to various agonists, platelet hyperactivity in diabetes may be in part due to an enhanced availability of this amine. Disturbances in peripheral serotonergic system together with platelet hyperaggregability may be associated with an increased incidence of cardiovascular complications in diabetes.
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PMID:[Blood platelet function, plasma serotonin and lipid metabolism in patients with diabetic nephropathy]. 852 96

In diabetic nephropathy there is accumulation of matrix proteins. Overproduction of these matrix proteins considered to be due to the phenotypic change of mesangial cell. In order to detect the phenotypic change of the mesangial cell, renal biopsy specimens from patients with diabetic nephropathy were stained with antibodies against various types of collagens and contractile-associated protein, caldesmon. Type III collagen was not stained in the glomerulus and type VI collagen showed mesangial pattern from normal controls. In diabetes, mesangial staining of type III collagen and increases in type VI collagen were observed in the mesangium. Increased mesangial staining of caldesmon was noted in the glomerulus from diabetic nephropathy in contrast to only vessel staining from normal controls. These results indicate that phenotypic changes are noted in the mesangium in diabetes. Expression of contractile-associated protein such as caldesmon, would serve as a useful marker to predict glomerulosclerosis.
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PMID:Phenotypic changes of the mesangium in diabetic nephropathy. 857 47

The direct relationship between elevated glucose concentrations and accelerated protein glycation has implicated increased glycation as a potential mechanistic link between hyperglycemia and the pathogenesis of diabetic nephropathy. Albumin modified by Amadori glucose adducts has been shown to stimulate collagen secretion by mesangial cells in vitro, and to contribute to the overproduction of glomerular mesangial matrix in vivo. To delineate mechanisms responsible for these effects, we examined the influence of glycated albumin on transcriptional activation of the alpha 1 (IV) collagen gene in renal glomerular mesangial cells. These experiments used a stably transfected reporter mesangial cell line that exhibits responses to media manipulations that are directionally parallel with those of non-transformed mesangial cells, and that expresses luciferase driven by 5'-flanking and first intron regions of the alpha 1 (IV) collagen gene. In these cells, purified glycated albumin stimulated collagen IV gene transcription, whereas glucose-free albumin did not. Further, glycated albumin induced a significant increase in mesangial cell collagen IV mRNA, assessed by Northern blot analysis and quantified by calculation of the ratio of collagen IV mRNA to 18S ribosomal RNA after densitometric scanning. The stimulation of collagen gene transcription and mRNA expression were both prevented by monoclonal antibodies known to specifically recognize Amadori-modified albumin. The findings indicate that glycated albumin promotes mesangial cell transcriptional activation and mRNA expression of the alpha 1 (IV) collagen gene and further implicate increased glycated albumin in diabetes in the pathogenesis of diabetic nephropathy.
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PMID:Albumin modified by Amadori glucose adducts activates mesangial cell type IV collagen gene transcription. 858 15

To clarify the diagnostic relevance of urinary type IV collagen (IV-C) and laminin in diabetic nephropathy, the excretion of these basement membrane proteins were determined by enzyme immunoassay in 172 non-insulin-dependent diabetic patients with different grades of nephropathy and 64 non-diabetic control subjects, and were evaluated in comparison with those of urinary albumin, N-acetyl-beta-D-glucosaminidase (NAG) and alpha 1-microglobulin (alpha 1MG). These excretions were also compared between a group of non-diabetic renal disease (NDRD) patients (n = 24) and a subgroup of the diabetic patients studied (n = 76), whose urinary albumin excretion (UAE) varied within the ranges of micro- and macroalbuminuria. Of the diabetic patients studied, 49.7%, 53.4% and 32.4% had raised urinary albumin, NAG and alpha 1 MG excretion, respectively. In these patients, 54% and 53% exceeded the upper limit of normal for urinary IV-C and laminin. The level of IV-C and laminin excretion and the prevalence of their abnormal excretion showed a trend to increase with increasing grade of nephropathy, as assessed by UAE. In the normoalbuminuric [UAE < 20 mg/g creatinine (Cr)] stage, 28.3% and 26.3% patients had raised urinary IV-C and laminin excretion, respectively. In this stage, the excretion values for IV-C and laminin also rose significantly even when the UAE was < or = 10 mg/g Cr (P < 0.05 and P < 0.005, respectively). There was a close linear relationship between IV-C and laminin excretion (r = 0.73, P < 0.0001), together with their significant relationships with albumin, NAG and alpha 1MG excretion. The relationship of urinary IV-C and laminin with urinary NAG and alpha 1MG excretion remained significant even in normoalbuminuric patients. The normoalbuminuric patients with raised NAG and/or alpha 1MG excretion also had a higher prevalence of raised IV-C and laminin excretion than those with normal NAG and alpha 1MG excretion. The excretion values for IV-C and laminin, and the excretion ratios for IV-C/albumin and laminin/albumin were significantly higher in diabetic patients with evidence of incipient and clinical nephropathy than in NDRD patients, though the two patient groups had a comparable level of serum Cr and UAE. We conclude that the measurement of urinary IV-C and laminin may have potential for the evaluation of diabetic nephropathy. Furthermore, their determination might be helpful for distinguishing diabetic versus non-diabetic etiologies of altered renal function in diabetic patients.
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PMID:Urinary excretion of type IV collagen and laminin in the evaluation of nephropathy in NIDDM: comparison with urinary albumin and markers of tubular dysfunction and/or damage. 859 60

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 investigated serum levels of type III procollagen aminopeptide (CIII), 7S type IV collagen (CIV), and tissue inhibitor of metalloproteinase (TIMP) in 33 patients with type II diabetes mellitus (DM) without uremia (serum creatinine less than 1.5 mg/dl). The patients were divided into three groups based on measurement of the urinary albumin excretion (UAE) index obtained during two morning outpatient clinic visits: non-proteinuric patients (n = 11), UAE index less than 2.26 mg/mmol Cr; patients with microalbuminuria (n = 15), UAE index of 2.26 - 22.6 mg/mmol Cr; and patients with proteinuria (n = 7), UAE index more than 22.6 mg/mmol Cr. Serum levels of CIV and TIMP in patients with microalbuminuria and proteinuria were significantly higher than non-proteinuric patients (ANOVA, p <0.05). Serum levels of CIII in patients with proteinuria were significantly higher than those in non-proteinuric patients (p < 0.05). There was a significant positive correlation between CIV and TIMP (r = 0.502, p < 0.003), but no correlation was observed between CIII and TIMP. These results demonstrated that serum CIII and CIV increases as diabetic nephropathy progresses in terms of increasing proteinuria in type II DM patients, suggesting feasibility and usefulness of measuring serum CIV and CIII in assessing diabetic nephropathy. The increase in TIMP may be, at least in part, a possible cause for the increase in serum CIV in type II DM patients.
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PMID:Serum type III, IV collagens and TIMP in patients with type II diabetes mellitus. 861 90

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


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