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)

Increased erythrocyte sodium-lithium countertransport activity has been implicated in the pathogenesis of diabetic nephropathy. However, its relationship to other cation membrane transport systems in incipient nephropathy is not yet clear. The present study was thus performed to: (1) explore associations between sodium-lithium countertransport and changes in the activity of other cation transport pathways and (2) to compare the sodium transport activities with clinical characteristics of insulin-dependent diabetic patients with and without evidence of incipient diabetic nephropathy. We measured erythrocyte sodium-lithium countertransport, passive sodium/potassium flux (at 1 degree C), adenine nucleotide content in intact erythrocytes and sodium/potassium-, magnesium- and calcium-dependent ATPase activity in erythrocyte membrane preparations from 34 insulin-dependent diabetic patients without microalbuminuria, 8 diabetic patients with microalbuminuria, and 8 age-matched healthy control subjects. Sodium-lithium countertransport was elevated in diabetic patients with normo- and microalbuminuria compared with control subjects [268 +/- 99 and 299(277-465), respectively, vs. 166 +/- 65 mumol/(1 cells x h)] and was positively correlated (r = 0.36, P < 0.05) with the albumin excretion rate. However, the activity of erythrocyte membrane ATPases was significantly decreased compared with control subjects. The ATP and ADP content was found to be significantly higher (P < 0.001) in erythrocytes from diabetic patients compared with control subjects (1,196 +/- 276 vs. 833 +/- 253 mumol/l cells and 353 +/- 97 vs. 255 +/- 64 mumol/l cells, respectively). The extent of erythrocyte potassium leakage correlated with hemoglobin A1c (r = 0.39, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Erythrocyte sodium-lithium countertransport, adenosine triphosphatase activity and sodium-potassium fluxes in insulin-dependent diabetes. 766 4

The authors present the results of evaluation of platelet aggregation by means of an automated system (on line detection of platelet aggregation curves) in 80 patients with diabetes mellitus type I. After global analysis no significant changes were found between controls, patients without diabetic nephropathy, and patients with incipient and clinically manifested nephropathy. However, as a result of our data, the area below the aggregatory curve is minimal in the group of patients with clinically manifested diabetic nephropathy. Additional changes of platelet aggregation were observed after dividing the followed set of patients dividing into homogenous subgroups according to their sex. The sensitivity of platelets after induction by ADP was found to be lower in male diabetics than in male controls. Likewise the area below the aggregatory curve and the transmittance of absolute maximum of platelet aggregation was lower in female diabetics than in female controls. In both cases diabetic nephropathy could have participated in platelet sensitivity changes. The authors' findings in the followed group of patients when compared with the described platelet hyperaggregability in diabetes approves the possibility of the platelet aggregatory polymorphism being present in these patients. With respect to these findings the examination of the platelet aggregation and its general parameters exactly justifies the usefulness of the antiaggregatory therapy. (Fig. 4, Ref. 15.)
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PMID:[Changes in thrombocyte aggregation in patients with type I diabetes]. 788 61

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

We hypothesize that poly (ADP-ribosyl)ation, that is, poly (ADP-ribose) polymerase (PARP)-dependent transfer of ADP-ribose moieties from NAD to nuclear proteins, plays a role in diabetic nephropathy. We evaluated whether PARP activation is present and whether two unrelated PARP inhibitors, 3-aminobenzamide (ABA) and 1,5-isoquinolinediol (ISO), counteract overexpression of endothelin-1 (ET-1) and ET receptors in the renal cortex in short-term diabetes. The studies were performed in control rats and streptozotocin-diabetic rats treated with/without ABA or ISO (30 and 3 mg x kg(-1) x day(-1), intraperitoneally, for 2 weeks after 2 weeks of diabetes). Poly (ADP-ribose) immunoreactivity was increased in tubuli, but not glomeruli, of diabetic rats and this increase was corrected by ISO, whereas ABA had a weaker effect. ET-1 concentration (ELISA) was increased in diabetic rats, and this elevation was blunted by ISO. ET-1, ET(A), and ET(B) mRNA (ribonuclease protection assay), but not ET-3 mRNA (RT/PCR), abundance was increased in diabetic rats, and three variables were, at least, partially corrected by ISO. ABA produced a trend towards normalization of ET-1 concentration and ET-1, ET(A), and ET(B) mRNA abundance, but the differences with untreated diabetic group were not significant. Poly(ADP-ribosyl)ation is involved in diabetes-induced renal overexpression of ET-1 and ET receptors. PARP inhibitors could provide a novel therapeutic approach for diabetic complications including nephropathy, and other diseases that involve the endothelin system.
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PMID:Diabetes-induced overexpression of endothelin-1 and endothelin receptors in the rat renal cortex is mediated via poly(ADP-ribose) polymerase activation. 1282 90

Both increased aldose reductase (AR) activity and oxidative/nitrosative stress have been implicated in the pathogenesis of diabetic nephropathy, but the relation between the two factors remains a subject of debate. This study evaluated the effects of AR inhibition on nitrosative stress and poly(ADP-ribose) polymerase (PARP) activation in diabetic rat kidney and high-glucose-exposed human mesangial cells. In animal experiments, control (C) and streptozotocin-diabetic (D) rats were treated with/without the AR inhibitor fidarestat (F, 16 mg kg(-1) day(-1)) for 6 weeks starting from induction of diabetes. Glucose, sorbitol, and fructose concentrations were significantly increased in the renal cortex of D vs C (p < 0.01 for all three comparisons), and sorbitol pathway intermediate, but not glucose, accumulation, was completely prevented in D + F. F at least partially prevented diabetes-induced increase in kidney weight as well as nitrotyrosine (NT, a marker of peroxynitrite-induced injury and nitrosative stress), and poly(ADP-ribose) (a marker of PARP activation) accumulation, assessed by both immunohistochemistry and Western blot analysis, in glomerular and tubular compartments of the renal cortex. In vitro studies revealed the presence of both AR and PARP-1 in human mesangial cells, and none of these two variables were affected by high glucose or F treatment. Nitrosylated and poly(ADP-ribosyl)ated proteins (Western blot analysis) accumulated in cells cultured in 30 mM D-glucose (vs 5.55 mM glucose, p < 0.01), but not in cells cultured in 30 mM L-glucose or 30 mM D-glucose plus 10 microM F. AR inhibition counteracts nitrosative stress and PARP activation in the diabetic renal cortex and high-glucose-exposed human mesangial cells. These findings reveal new beneficial properties of the AR inhibitor F and provide the rationale for detailed studies of F on diabetic nephropathy.
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PMID:Aldose reductase inhibition counteracts nitrosative stress and poly(ADP-ribose) polymerase activation in diabetic rat kidney and high-glucose-exposed human mesangial cells. 1663 35

The activation of the poly(ADP-ribose) polymerase (PARP) plays an important role in the pathophysiology of various diseases associated with oxidative stress. We found increased amounts of poly(ADP) ribosylated proteins in diabetic kidneys of Lepr(db/db) (BKsJ) mice, suggesting increased PARP activity. Therefore, we examined the effects of two structurally unrelated PARP inhibitors (INO-1001 and PJ-34) on the development of diabetic nephropathy of Lepr(db/db) (BKsJ) mice, an experimental model of type 2 diabetes. INO-1001 and PJ-34 were administered in the drinking water to Lepr(db/db) mice. Both INO-1001 and PJ-34 treatment ameliorated diabetes-induced albumin excretion and mesangial expansion, which are hallmarks of diabetic nephropathy. PARP inhibitors decreased diabetes-induced podocyte depletion in vivo and blocked hyperglycemia-induced podocyte apoptosis in vitro. High glucose treatment of podocytes in vitro led to an early increase of poly(ADP) ribosylated modified protein levels. Reactive oxygen species (ROS) generation appears to be a downstream target of hyperglycemia-induced PARP activation, as PARP inhibitors blocked the hyperglycemia-induced ROS generation in podocytes. INO-1001 and PJ-34 also normalized the hyperglycemia-induced mitochondrial depolarization. PARP blockade by INO-1001 and PJ-34 prevented hyperglycemia-induced nuclear factor-kappaB (NFkappaB) activation of podocytes, and it was made evident by the inhibitor of kappaBalpha phosphorylation and NFkappaB p50 nuclear translocation. Our results indicate that hyperglycemia-induced PARP activation plays an important role in the pathogenesis of glomerulopathy associated with type 2 diabetes and could serve as a novel therapeutic target.
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PMID:Poly(ADP-ribose) polymerase inhibitors ameliorate nephropathy of type 2 diabetic Leprdb/db mice. 1706 36

Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1) (also known as CD39) is the dominant vascular ectonucleotidase. By hydrolyzing ATP and ADP to AMP, ENTPD1 regulates ligand availability to a large family of P2 (purinergic) receptors. Modulation of extracellular nucleotide metabolism is an important factor in several acute and subacute models of vascular injury. We hypothesized that aberrant nucleotide signaling would promote chronic glomerular injury in diabetic nephropathy. Inducing diabetes in ENTPD1-null mice with streptozotocin resulted in increased proteinuria and more severe glomerular sclerosis compared with matched diabetic wild-type mice. Diabetic ENTPD1-null mice also had more glomerular fibrin deposition and glomerular plasminogen activator inhibitor-1 (PAI-1) staining than wild-type controls. In addition, ENTPD1-null mice showed increased glomerular inflammation, in association with higher levels of monocyte chemoattractant protein-1 (MCP-1) expression. Mesangial cell PAI-1 and MCP-1 mRNA expression were upregulated by ATP and UTP but not ADP or adenosine in vitro. The stable nucleotide analog ATPgammaS stimulated sustained expression of PAI-1 and MCP-1 in vitro, whereas the stable adenosine analog NECA [5'-(N-ethylcarboxamido)adenosine] downregulated expression of both genes. Extracellular nucleotide-stimulated upregulation of MCP-1 is, at least in part, protein kinase C dependent. We conclude that ENTPD1 is a vascular protective factor in diabetic nephropathy that modulates glomerular inflammation and thromboregulation.
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PMID:The vascular ectonucleotidase ENTPD1 is a novel renoprotective factor in diabetic nephropathy. 1747 21

Tranilast, N-(3,4-demethoxycinnamoyl)-anthranilic acid, is an anti-allergic agent identified as an inhibitor of mast cell degranulation. Recently, tranilast was shown to decrease albuminuria in a rat model of diabetic nephropathy and to ameliorate vascular hypertrophy in diabetic rats, suggesting that it may be clinically useful in the treatment of diabetic complications. However, the effects of tranilast on glucose tolerance have not been elucidated. Thus, the aim of this study is to investigate the effect of tranilast on insulin secretion in pancreatic beta-cells. Treatment with tranilast significantly suppressed insulin secretion in INS-1E cells and rat islets induced by 16.7 mmol/l glucose. Furthermore, tranilast inhibited tolbutamide-induced insulin secretion. Treatment with tranilast increased (86)Rb (+) efflux from COS-1 cells in which pancreatic beta-cell-type ATP-sensitive K (+) (K (ATP)) channels were reconstructed and suppressed the cytosolic ATP/ADP ratio in INS-1E cells. Interestingly, treatment with tranilast enhanced glucose uptake in INS-1E cells. In the present study, we demonstrated that tranilast inhibited glucose- and tolbutamide-induced insulin secretion through the activation of K (ATP) channels in pancreatic beta-cells.
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PMID:Tranilast inhibits glucose-induced insulin secretion from pancreatic beta-cells. 1850 Jun 75

The role of ADP-ribosyl cyclases (ADPR-cyclases) in diabetic nephropathy was investigated. ADPR-cyclases synthesize cADP-ribose (cADPR), a Ca(2+)-mobilizing second messenger, and are stimulated by G protein-coupled receptors. We have previously reported that ADPR-cyclases can be activated by ANG II and showed that a specific kidney ADPR-cyclase inhibitor, 4,4'-dihydroxyazobenzene (DHAB), can protect ANG II-mediated mesangial cell growth (Kim SY, Gul R, Rah SY, Kim SH, Park SK, Im MJ, Kwon HJ, Kim UH. Am J Physiol Renal Physiol 294: F982-F989, 2008). In this study, we examined the preventive effect of DHAB on glomerular injury in streptozotocin (STZ)-induced diabetic mice. Male mice were randomly assigned to normal control and diabetic groups of comparable age. A diabetic group received 45 microg/kg of DHAB for 6 wk via daily intraperitoneal injections. Several nephropathy parameters were improved in the DHAB-treated diabetic group compared with the diabetic group, including urinary albumin (diabetic, 44.6 +/- 5.1 vs. treated, 33.9 +/- 3.9 microg/day), creatinine clearance (diabetic, 0.72 +/- 0.03 vs. treated, 0.83 +/- 0.04 ml.min(-1).100 g(-1)), ratio of kidney to body weight (diabetic, 2.5 +/- 0.04 vs. treated, 1.4 +/- 0.04), and mesangial matrix expansion (diabetic, 13.9 +/- 2.2 vs. treated, 8.5 +/- 2.0%). These results indicate that kidney function in STZ-induced diabetes was improved by DHAB administration. Furthermore, DHAB inhibited phosphorylation of Akt and nuclear factor of activated T cell 3 nuclear translocation, as well as ADPR-cyclase activity and cADPR production, which were increased in the kidneys of the diabetic group. In addition, DHAB treatment decreased fibrosis marker protein expression and glomerular hypertrophy in the diabetic kidney. These findings indicate a crucial role that ADPR-cyclase signaling plays in the renal pathogenesis of diabetes and provide a therapeutic tool for the treatment of renal diseases.
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PMID:Role of kidney ADP-ribosyl cyclase in diabetic nephropathy. 1907 39

Patients with diabetes mellitus (DM) have increased platelet activation compared to non-diabetic controls. Platelet hyperreactivity has been associated with adverse cardiovascular outcomes in Type 2 DM, and with diabetic nephropathy. We investigated the relationship between platelet activation and nephropathy in Type 1 DM. Patients with Type 1 DM and diabetic nephropathy (n = 35), age- and sex-matched Type 1 DM patients with persistent normoalbuminuria (n = 51), and healthy age- and sex-matched controls (n = 30) were studied. Platelet surface P-selectin, platelet surface activated GPIIb/IIIa, monocyte-platelet aggregates (MPAs) and neutrophil-platelet aggregates (NPAs) were measured by whole blood flow cytometry as markers of platelet activation. Platelet reactivity was assessed in response to exogenously added ADP and thrombin receptor activating peptide (TRAP). Platelet surface P-selectin (basal and in response to 0.5 or 20 microM ADP) was higher in nephropathy patients compared with normoalbuminuric patients (P = 0.027), and non-diabetic controls (P = 0.0057). NPAs were higher in nephropathy patients compared to normoalbuminuric patients (P = 0.0088). MPAs were higher in nephropathy patients compared to non-diabetic controls (P = 0.0075). There were no differences between groups in activated GPIIb/IIIa or in response to TRAP at any end-point. More patients with nephropathy received aspirin (71.4%) compared to normoalbuminuric patients (27.4%) (P < 0.0001). Type 1 diabetic nephropathy, as compared with normoalbuminuria, is associated with circulating activated platelets and platelet hyperreactivity to ADP, despite the confounding variable of more nephropathy patients receiving aspirin. This platelet activation is likely to contribute to the known increased risk of cardiovascular events in patients with diabetic nephropathy.
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PMID:Nephropathy in type 1 diabetes is associated with increased circulating activated platelets and platelet hyperreactivity. 1985 91

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