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

The decline in glomerular filtration rate (GFR) in long-term diabetes in humans and animals in preceded by a period of hyperfiltration that may be responsible for it. The mediators of the increase in glomerular filtration are unknown, but recent studies suggest a prominent role for prostaglandins. To test the hypothesis that prostaglandins mediate early hyperfiltration and contribute to the progression of diabetic nephropathy, we examined the effects of long-term aspirin (ASA) treatment on whole kidney GFR and renal prostaglandin E2 (PGE2) synthesis in control and diabetic rats 8 days and 16 weeks after streptozocin administration. The rats were divided into four groups, control, control with ASA (C/ASA), diabetic, and diabetic with ASA (D/ASA). We found that 8 days after streptozocin treatment, PGE2 synthesis and GFR were increased in diabetic rats. ASA treatment inhibited renal prostaglandin synthesis and prevented the GFR increase. ASA given to control rats reduced PGE2 synthesis without changing GFR. In the 16-week study diabetic rats had lower GFR and increased renal PGE2 synthesis. Diabetic rats also had thickened glomerular basement membrane compared with control rats. By contrast GFR did not fall and thickening of the glomerular basement membrane did not occur in diabetic rats receiving ASA. ASA had no effect on GFR or glomerular basement membrane in normal rats but decreased renal PGE2 synthesis. The data demonstrate that aspirin prevents early hyperfiltration and prevents the fall in GFR and glomerular basement membrane thickening that occurs over time in diabetic rats. Inhibition of PGE2 synthesis by aspirin, or some other effect of aspirin, may be responsible for the protection observed.
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PMID:Effect of aspirin on experimental diabetic nephropathy. 347 95

These studies evaluated the contribution of insulin to the development of the abnormal mesangial matrix that characterizes diabetic nephropathy and is common to mesangial cells in culture. Glomeruli were isolated from a single rat and divided into two aliquots. In one set (SI-MC), the insulin contained in the medium was only that contributed by the fetal calf serum (20%). For the other set, the tissue culture medium was supplemented with 1 microM insulin (SI+MC). Mesangial cell outgrowths from each condition were isolated, cloned, and propagated. At passage 4, mesangial cells were characterized by morphology and cell markers, and compared in terms of composition and appearance of the secreted extracellular matrix. SI-MC grew in nests of cells surrounded by a thin layer of matrix that was rich in collagen IV. In contrast, mesangial cells supplemented with insulin aggregated into macroscopic "hillocks" rich in collagens I and III as described previously. Insulin (1 microM) or IGF-I (0.1 microM) was subsequently added to the medium of SI-MC. Insulin, but not IGF-I, induced a change in culture morphology and collagen accumulation characteristic of SI+MC. In contrast to SI+MC, SI-MC express insulin receptors and at physiologic concentrations insulin is a more potent stimulator of MC proliferation than is IGF-I. Insulin-induced changes in the collagenous composition of the accumulated ECM were directionally correlated with the rate of collagen I synthesis measured by biosynthetic labeling experiments and collagens III and IV as determined by ELISA. These data demonstrate that insulin alters the phenotype of mesangial cells in culture and their expression of interstitial and basement membrane collagens. These observations implicate insulin as a factor in the pathogenesis of mesangial matrix accumulation in diabetic nephropathy. Furthermore, a method for culturing mesangial cells that accumulate an extracellular matrix that is similar in composition to normal mesangial matrix provides a new model system for future studies of mesangial cell biology.
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PMID:Induction of nodular sclerosis by insulin in rat mesangial cells in vitro: studies of collagen. 773 Nov 54

We have studied cardiovascular and catecholamine responses to induction of anaesthesia and tracheal intubation in 13 patients with diabetic nephropathy, in 12 patients with uraemia of other origin and in 12 ASA I control patients. All uraemic patients were undergoing renal transplantation. Cardiovascular autonomic function tests indicated that severe autonomic neuropathy was common in the diabetic patients; less severe impairment of autonomic function was found in the non-diabetic uraemic patients. The systolic pressor response to intubation was greater in diabetic uraemic patients than in the other groups (P < 0.05). Both uraemic groups had higher plasma catecholamine concentrations than the ASA I patients both before and after induction of anaesthesia. The increased plasma concentrations of catecholamines in the uraemic patients may be a result of impaired clearance of catecholamines and higher sympathoadrenal activity needed to maintain cardiac function. The normal systolic pressor response to tracheal intubation in the uraemic patients indicates that the capacity of the cardiovascular system to respond to a stressful stimulus was preserved in these patients also, in spite of autonomic neuropathy. The greater response in the diabetic group may be caused by increased sensitivity to catecholamines and loss of autonomic control.
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PMID:Haemodynamic and catecholamine responses to induction of anaesthesia and tracheal intubation in diabetic and non-diabetic uraemic patients. 788 Jul 9

Several glucose transporters have recently been identified in glomeruli, and in cultured glomerular cells. These include the facilitative glucose transporter isoforms GLUTs 1, 3 and 4, and sodium-glucose cotransport activity with characteristics of SGLT1. GLUTs 1, 3 and 4 are all high affinity, low capacity, facilitative glucose transporters which typically would be saturated at or near physiologic glucose concentrations. The SGLT transporter of mesangial cells is also a high affinity transporter which similarly could be saturated under normal glucose conditions. This suggests that in order for mesangial cells to take up excessive quantities of glucose in diabetes, changes in glucose transporter expression, translocation or activity may be required. Accordingly, recent investigations discovered positive-feedback regulation of the mesangial cell GLUT1 transporter by glucose, and a regulatory role for GLUT1 in glucose metabolism and extracellular matrix synthesis. Future investigations of glucose transporters in the pathogenesis of diabetic renal disease will now likely proceed in multiple directions, including but not limited to: (1) examination of their regulation by growth factors implicated in diabetic nephropathy, and the resultant effects on ECM synthesis; (2) determination of the mechanisms by which GLUT1 regulates the expression of aldose reductase, PKC, GLUT1, and other genes in the mesangial cell; and (3) Suppression of glucose transporters in attempts to prevent high glucose-induced diabetic glomerulosclerosis.
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PMID:Glucose transporters of the glomerulus and the implications for diabetic nephropathy. 928 9

Inhibitors of angiotensin converting enzyme (ACE inhibitors) have been introduced more than fifteen years ago into the treatment of hypertension, congestive heart failure, myocardial infarction and diabetic nephropathy. The therapeutic success is related to their action in reduction of plasma and tissue angiotensin II concentrations and potentiation of endogenous kinins. They are able to improve myocardium metabolic status, prevent cardiac hypertrophy, limit myocardial infarct size, and thus prevent heart failure. Since 1987 ACE inhibitors are introduced in the clinical practice in our clinic. We introduced the therapy with lisinopril (Lopril), in 70% of patients among 2855 patients that were admitted in Coronary Care Unit in 1997 and 1998. Lisinopril was introduced as soon as the patient was admitted, together with fibrinolitic, Heparin and Aspirin therapy. Since that time we noticed decrease in postinfarction heart failure in comparison to previous years. We recommend permanent therapy with a small doses of ACE inhibitors in patients with heart infarction.
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PMID:[Converting enzyme inhibitors in acute myocardial infarct and heart failure]. 1035 28

Diabetic nephropathy is characterized by the rapid onset of hypertrophy and ECM expansion. Previously, we showed that calcineurin phosphatase is required for hypertrophy and ECM synthesis in cultured mesangial cells. Therefore, we examined the effect of calcineurin inhibition on renal hypertrophy and ECM accumulation in streptozotocin-induced diabetic rats. After 2 wk of diabetes, calcineurin protein was increased in whole cortex and glomeruli in conjunction with increased phosphatase activity. Daily administration of cyclosporin A blocked accumulation of both calcineurin protein and calcineurin activity. Also associated with calcineurin upregulation was nuclear localization of the calcineurin substrate NFATc1. Inhibition of calcineurin reduced whole kidney hypertrophy and abolished glomerular hypertrophy in diabetic rats. Furthermore, calcineurin inhibition substantially reduced ECM accumulation in diabetic glomeruli but not in cortical tissue, suggesting a differential effect of calcineurin inhibition in glomerular vs. extraglomerular tissue. Corresponding increases in fibronectin mRNA and transforming growth factor-beta mRNA were observed in tubulointerstitium but not in glomeruli. In summary, calcineurin plays an important role in glomerular hypertrophy and ECM accumulation in diabetic nephropathy.
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PMID:Calcineurin is activated in diabetes and is required for glomerular hypertrophy and ECM accumulation. 1238 27

The metabolic syndrome is intended to identify patients who have increased risk of diabetes and/or a cardiac event due to the deleterious effects of weight gain, sedentary lifestyle, and/or an atherogenic diet. The National Cholesterol Education Program's Adult Treatment Panel III definition uses easily measured clinical findings of increased abdominal circumference, elevated triglycerides, low high-density lipoprotein-cholesterol, elevated fasting blood glucose and/or elevated blood pressure. Three of these five are required for diagnosis. The authors also note that other definitions of metabolic syndrome focus more on insulin resistance and its key role in this syndrome. This review focuses on how treatment might affect each of the five components. Abdominal obesity can be treated with a variety of lower calorie diets along with regular exercise. Indeed, all of the five components of the metabolic syndrome are improved by even modest amounts of weight loss achieved with diet and exercise. For those with impaired fasting glucose tolerance, there is good evidence that a high fiber, low saturated fat diet with increased daily exercise can reduce the incidence of diabetes by almost 60%. Of note, subjects who exercise the most, gain the most benefit. Metformin has also been shown to be helpful in these subjects. Thiazolidinedione drugs may prove useful, but further studies are needed. Although intensified therapeutic lifestyle change will help the abnormal lipid profile, some patients may require drug therapy. This review also discusses the use of statins, fibrates, and niacin. Likewise, while hypertension in the metabolic syndrome benefits from therapeutic lifestyle change, physicians should also consider angiotensin converting enzyme inhibitor drugs or angiotensin receptor blockers, due to their effects on preventing complications of diabetes, such as progression of diabetic nephropathy and due to their effects on regression of left ventricular hypertrophy. Aspirin should be considered in those with at least a 10% risk of a coronary event over 10 years. Finally, three related conditions, nonalcoholic fatty liver disease, polycystic ovary syndrome and protease inhibitor associated lipodystrophy improve with therapeutic lifestyle change. Although metformin is shown to be useful with polycystic ovary syndrome, the data supporting drug therapy for the other syndromes is less convincing. More robust studies are needed before any firm recommendations can be made.
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PMID:Treatment of metabolic syndrome. 1515 70

Plasminogen activator inhibitor-1 (PAI-1) may contribute to renal fibrosis because of its involvement in matrix (ECM) accumulation through inhibition of plasmin-dependent ECM degradation. The aim of this study is to determine urinary PAI-1 concentrations and its intrarenal localization in patients with various renal diseases and to identify inducers for PAI-1 expression in human cultured proximal renal tubular cells (HRCs). Urinary PAI-1 concentrations were significantly higher in patients with overt diabetic nephropathy (DN, n=36) than in proliferative glomerulonephritis (PGN, n=8), nephrotic syndrome (NS, n=10) and healthy controls (n=12). Urinary PAI-1 concentrations (ng/gCr) were directly correlated with urinary N-acetyl glucosaminidase (NAG) levels (r=0.58, p<0.05). As for intrarenal localization of PAI-1 antigen, strong stainings for PAI-1 were observed in proximal tubular cells of renal biopsy samples from patients with DN, while no stainings for PAI-1 were found in renal tissues of PGN or NS. Immunoblot analysis revealed the presence of PAI-1 protein in whole cell lyzates from HRCs grown to semiconfluency. Exposure of growth-arrested HRCs with hypoxia (1% O2) or TNF-alpha (10 ng/ml) for 24 hours increased the secretion rate of PAI-1 protein by about 2.0-fold, while 24-hour treatment with high glucose (450 mg/dl) did not increase PAI-1 secretion at all, compared with that of the control cells under normal glucose (100 mg/dl) and normoxia (18% O2). These findings suggest that PAI-1 expression is upregulated especially in the proximal renal tubular cells of DN, which may be explained partially by hypoxia and inflammatory cytokines but not high glucose.
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PMID:[Diabetic nephropathy and plasminogen activator inhibitor 1 in urine samples]. 1528 63

Changes in glucose transporter expression in glomerular cells occur early in diabetes. These changes, especially the GLUT1 increase in mesangial cells, appear to play a pathogenic role in the development of ECM expansion and perhaps other features of diabetic nephropathy. In addition, it appears that at least some diabetic patients may be predisposed to nephropathy because of polymorphisms in their GLUT1 genes. GLUT1 overexpression leads to increased glucose metabolic flux which in turn triggers the polyol pathway and activation of PKC alpha and B1. Activation of these PKC isoforms can lead directly to AP-1 induced increases in fibronectin expression and ECM accumulation. Other, more novel effects of GLUT1 on cellular hypertrophy and injury could also promote changes of diabetic nephropathy. Strategies to prevent GLUT1 overexpression could ameliorate or prevent the progression of diabetic nephropathy.
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PMID:Glucose transporters in diabetic nephropathy. 1571 66

PPAR-gamma ligands, including thiazolidinediones, have recently become clinically available for treating insulin-resistant diabetes mellitus. Accumulating evidence suggests that these drugs not only significantly improve insulin sensitivity but also may have antiproteinuric effects in genetically obese diabetic rodents and patients with type II diabetes and diabetic nephropathy. Moreover, troglitazone reduced expression of ECM proteins and transforming growth factor-beta in glomeruli from streptozotocin-induced diabetic rats. Many other properties including antiproteinuric, hemodynamic, and antihypertensive effects in insulin-dependent diabetes mellitus suggest that PPAR-gamma ligands might have a direct, beneficial renal effect, independent of their capacity to improve glucose tolerance. Besides their antidiabetic effects, thiazolidinediones have been shown to lower blood pressure in diabetic patients with hypertension and patients with diabetic nephropathy through multiple mechanisms. Several studies showed the efficacy of PPAR-gamma agonists to ameliorate the progression of glomerulosclerosis. The effect is independent of insulin effects and could only be partially due to lipid effects. These renal protective effects of PPAR-gamma agonists suggest that they may provide a novel intervention strategy to prevent vascular and glomerular sclerosis.
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PMID:PPAR-gamma-agonists' renal effects. 1624 47


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