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)

To study the effect of high glucose on the production of type IV collagen and laminin P1 from the cultured human umbilical vein endothelial cells (HUVEC), we measured type N collagen and laminin P1 from HUVEC that were cultured under different conditions. The concentrations of type IV collagen in the cultured medium for high glucose (30 mM D-glucose) were significantly higher than those for low glucose (5.6 mM D-glucose), L-glucose (30 mM), or mannitol (30 mM). The increase of type IV collagen was dependent on the glucose concentration in the medium. The contents of type IV collagen in the cultured cells were also increased in high-glucose incubation compared with low glucose or L-glucose incubation. In contrast, the levels of laminin P1 in the medium cultured with high glucose were similar to those with low glucose or L-glucose. These results suggest that the increased production of type IV collagen may contribute to the thickening of basement membranes and may be linked to the development of diabetic nephropathy.
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PMID:Glucose-induced production of type IV collagen and laminin P1 from cultured human umbilical vein endothelial cells. 177 48

Experimental galactosemia, induced by feeding rats a galactose enriched diet, reproduces many of the neural and ocular complications of diabetes and induces protein glycation and polyol accumulation. To explore the role of these biochemical abnormalities in the pathogenesis of glomerular injury, adult male Sprague-Dawley rats were placed on either a 50% galactose or 50% glucose diet. After two months, galactose fed rats exhibited elevated excretory rates of protein, albumin, and IgG. Blebbing and ballooning of the glomerular epithelial cells were apparent in rats on the galactose supplemented diet. Morphometric evaluation of the glomeruli revealed an increase in the fractional and absolute volume of the glomerular epithelial cells, but glomerular and mesangial volume, basement membrane thickness, and epithelial foot process width were similar on the two diets. Glycation of the glomerular basement membrane was increased in the galactose fed rats. Glomerular micropuncture revealed similar glomerular pressures and flow rates on the two diets. Aldose reductase inhibition had no effect on galactose induced proteinuria. These results suggest that biochemical abnormalities such as protein glycation may be important in the pathogenesis of altered glomerular permselectivity in diabetic nephropathy.
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PMID:Functional and structural alterations of the glomerular permeability barrier in experimental galactosemia. 191 Jan 23

The purpose of the present study is to determine polyols and sugars in glomeruli obtained from streptozotocin (STZ) diabetic rats. Sixty milligram per kg body weight of STZ was injected to Sprague-Dawley male rats and then the animals were sacrificed 4 and 12 weeks after the injection. One group of STZ diabetic rats was treated with 8-14 units of NPH insulin for 3 weeks. Glomeruli were isolated by sieving methods. The concentration of polyols and sugars was measured by gas chromatography mass spectrometry. The levels of glucose, sorbitol, fructose, mannose, ribitol and erythritol in the glomeruli were significantly higher in 4- or 12-week diabetic rats than those in control rats, whereas the level of scyllo-inositol was decreased. In insulin treated 4-week diabetic rats, the levels of all polyols but scyllo-inositol were significantly decreased compared with untreated diabetic rats. The level of myo-inositol in glomeruli of 12-week diabetic rats was significantly higher than those of control rats, whereas that of erythritol was decreased. The urinary N-acetyl glucosaminidase activity as well as creatinine clearance was increased in 4- and 12-week diabetic rats. Urinary protein was also increased in 12-week diabetic rats. These findings suggest that the alterations of polyol metabolism in glomeruli of diabetes may play an important role in the pathogenesis and/or progression of diabetic nephropathy. It is likely that treatment with insulin improves the alteration of polyol metabolism in the glomeruli in early stages of diabetes.
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PMID:[Alteration of polyol metabolism in glomeruli of streptozotocin diabetic rats--analysis by gas chromatography-mass spectrometry]. 214 67

We examined the clinical usefulness determined by polyacrylamide gel electrophoresis, followed by reaction with peroxidase-coupled lectins using urinary glycoproteins for diabetic nephropathy in 20 patients with diabetes mellitus. Lectins used were Triticum vulgaris (WGA), Phaseolus vulgaris (PHA-E4), Dolichos biflorus (DBA), and Lens culinaris (LCA), which have high affinity for beta 1----4N-acetyl-D-glucosamine (GlcNAc beta 1----4GlcNAc), N-acetyl-D-galactosamine (GalNAc), alpha-galactosamine (alpha-GalNAc), and alpha-mannose (alpha-Man) residues, respectively. Electrophoretic patterns of urinary glycoproteins clearly showed the presence of lectin-reactive glycoproteins with molecular weights lower than that of albumin. The molecular weight of the main bands reacted with WGA, PHA-E4 or LCA were 50,000 and 38,000, and increased with the progress of diabetic nephropathy. WGA reacted strongly with many glycoproteins having a wide range of molecular weights. LCA and PHA-E4 reacted preferentially with glycoproteins of molecular weights glycoproteins of molecular weights lower than 50,000, but no reaction was observed by DBA. These results suggest that low molecular urinary glycoproteins have abundant carbohydrate residues such as GlcNAc beta 1----4GlcNAc, GalNAc, and alpha-Man. The excretion of low molecular weight glycoproteins with high affinities for some lectins suggests functional impairment in diabetic nephropathy.
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PMID:[Electrophoretic analysis of urinary glycoproteins in diabetic nephropathy using peroxidase-lectins]. 248 79

The effect of 30% galactose feeding on kidney function and structure was compared to the effect of streptozotocin-induced diabetes in the rat. In the galactose-fed rats there was increased urine volume (500%), creatinine clearance (40%), urinary albumin excretion (100%), urinary N-acetyl glucosaminidase (600%) and relative kidney weight (21%). These changes were similar to that observed in streptozotocin-induced diabetic animals. Galactitol in the kidney cortex of galactose-fed rats was increased 4 times similar to that observed for sorbitol in the streptozotocin-induced diabetic animals. Glycosylated hemoglobins were also increased in both galactose-fed animals and streptozotocin-treated animals. These data suggest that galactose feeding may be a useful model for investigating some aspects of diabetic nephropathy.
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PMID:Galactosemic nephropathy in the rat. 365 1

To evaluate the role of hyperglycemia in the pathogenesis of diabetic nephropathy, the kidneys from dogs experimentally galactosemic for 5 yr have been compared with the kidneys from age-matched normal dogs and dogs with alloxan-induced diabetes for 5 yr. The width of glomerular capillary basement membrane and the quantity of plasma protein immunohistochemically demonstrable in the basement membrane were supranormal in the galactosemics, as they were in the diabetics. In contrast, kidney weight, mesangial volume, and the prevalence of obliterated glomeruli, glomerular exudates, and mesangial nodules in the galactosemic animals were comparable to those of normal animals and clearly were less than observed in the insulin-deficient diabetic animals. These galactosemic dogs are known to have developed a retinopathy morphologically indistinguishable from that of diabetic patients and dogs. Thus, galactosemia sufficient to produce diabetic-like lesions in the glomerular basement membrane and retina was found to be nevertheless insufficient to elicit several renal abnormalities that are typical of diabetes. The polyol concentration in erythrocytes was greater than normal in the galactosemics and the diabetics and was greatest in the galactosemics. The absence of mesangial expansion, glomerular obliteration, and nephromegaly in galactose-fed dogs raises the possibility that these abnormalities in diabetes are not a result of excessive polyol pathway activity.
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PMID:Kidney morphology in experimental hyperglycemia. 380 34

The Fanconi-Bickel syndrome is a rare inherited disorder of metabolism characterized by hepatic glyconeogenesis, galactose intolerance, renal Fanconi syndrome with nephromegaly, and glycogen accumulation in proximal renal tubular cells. An 8-year-old patient with this disease and severe rickets due to medically resistant hypophosphatemia was found to have the previously unrecognized complication of renal glomerular hyperfiltration, microalbuminuria, and diffuse glomerular mesangial expansion. Similar to patients with glucose-6-phosphatase deficiency, the glomerular disease in this patient resembles incipient diabetic nephropathy. The Fanconi syndrome may be due to the defective transport of glucose at the proximal tubular basolateral membrane, which results in accumulation of glucose and secondarily glycogen within tubular cells. Since the metabolic defect, as evidenced by glycogen accumulation, selectively involves proximal renal tubular cells in the kidney of patients with Fanconi-Bickel syndrome and glucose-6-phosphatase deficiency, the abnormalities in renal glomerular hemodynamics and mesangial construct in these rare diseases are likely due to renal tubular factors, if the mechanism originates in the kidney. A delineation of these phenomena may further our understanding of the pathogenesis of diabetic nephropathy.
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PMID:Diabetes-like renal glomerular disease in Fanconi-Bickel syndrome. 763 12

Interstitial fibrosis is a marker of progression of renal impairment in diabetic nephropathy. Transforming growth factor (TGF)-beta 1 is one of a group of pro-fibrotic cytokines and growth factors that have been associated with the development of interstitial fibrosis. We have examined the modulating influence of glucose on the production of TGF-beta 1 by cultured human proximal tubular cells. Incubation of growth-arrested human proximal tubular cells (HPTC) (72 hours in serum free medium) in 25 mmol/L D-glucose resulted in increased expression of TGF-beta 1 mRNA (as assessed by reverse transcription polymerase chain reaction). This was apparent after 6 hours and increased up to 120 hours exposure. TGF-beta 1 secretion, however, as measured by specific enzyme-linked immunoassay, was unaffected by exposure to 25 mmol/L D-glucose. Sequential stimulation of HPTC, first with 25 mmol/L D-glucose for 48 hours and then with platelet-derived growth factor (PDGF) isoforms, resulted in a dose-dependent secretion of TGF-beta 1. Pre-exposure to 5 mmol/L D-glucose or 25 mmol/L L-glucose did not prime for TGF-beta 1 release. At 50 ng/ml PDGF this effect was greatest for the AA isoform (AA 31.4 +/- 7.1, AB 20.98 +/- 8.9, BB 7.8 +/- 2.2, P < 0.05 for all versus control, n = 3, mean +/- SEM ng/10(6) cells/24 hours). These effects were blocked by the addition of antibody to the PDGF alpha-receptor. TGF-beta 1 secretion was inhibited in a dose-dependent manner by pretreatment with cyclohexamide, but was not affected by pretreatment with actinomycin D. Stimulation of HPTC with a single dose of PDGF induced TGF-beta 1 mRNA; however, only after application of a second dose of PDGF (after TGF-beta 1 mRNA induction) did TGF-beta 1 protein secretion occur. We also demonstrated that PDGF stimulation of HPTC induced an inherently more stable TGF-beta 1 mRNA transcript. These findings demonstrate that elevated D-glucose concentration alone is insufficient to lead to increased TGF-beta 1 secretion by HPTC despite increased mRNA expression. However, application of a second stimulus such as PDGF, when TGF-beta 1 mRNA expression is increased, leads to increased protein synthesis and secretion of TGF-beta 1. This implies that elevated glucose concentrations might prime proximal tubular cells for TGF-beta 1 synthesis and thus contribute to the development of interstitial fibrosis.
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PMID:Elevated D-glucose concentrations modulate TGF-beta 1 synthesis by human cultured renal proximal tubular cells. The permissive role of platelet-derived growth factor. 763 30

A role for aldose reductase-mediated production of polyol in the aetiology of diabetic nephropathy has been supported by both animal and clinical studies. In the renal medulla, the rate of polyol production is influenced in part by regulated changes in the level of aldose reductase gene expression. However, little is known about the expression of aldose reductase in the renal cortex. In this study, we evaluated the regulation of aldose reductase gene expression in the renal cortex and medulla in response to galactose feeding. Four groups of rats (n = 6) were treated for 9 weeks with control or galactose diet in the presence or absence of sorbinil, an aldose reductase inhibitor. In the renal medulla, galactose treatment produced a significant (p < 0.01) decrease in aldose reductase mRNA, to approximately 10% of control levels. Coadministration of sorbinil partially prevented the effect of galactose feeding on medullary aldose reductase mRNA (to 43% of control). Under basal conditions, the concentration of aldose reductase mRNA in the cortex was only 1% that of the renal medulla. Galactose feeding significantly reduced cortical aldose reductase mRNA by 29% relative to control (p < 0.01), and this was completely reversed by addition of sorbinil. Sorbinil administration to rats fed a control diet also decreased aldose reductase expression in the renal medulla and cortex. These results demonstrate that galactose feeding results in dynamic, polyol-dependent regulation of aldose reductase gene expression in the renal cortex as well as the medulla.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of aldose reductase gene expression in renal cortex and medulla of rats. 774 29

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


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