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)

We tested the hypothesis that dysfunction of vascular endothelium, indicated by an increase in plasma level of von Willebrand factor (vWF), is present in patients with insulin-dependent diabetes mellitus (IDDM) who develop diabetic nephropathy (DN). DN was classified as absent (urinary albumin excretion [UAE] rate less than 15 microgram/min), incipient (UAE rate 15-200 micrograms/min), or clinical (UAE rate greater than 200 micrograms/min). We followed a cohort of 59 patients for a median of 3 yr. At baseline, 52 patients had no DN, 6 had incipient DN, and 1 had clinical DN. At follow-up, 38 patients had no DN (group 1). Incipient DN had developed in 14 patients and worsened in 3 patients. Clinical DN had worsened in 1 patient. Together, these 18 patients comprised group 2. A decrease in UAE was observed in the remaining three patients with incipient DN at baseline (group 3). In group 1, vWF--measured by immunoelectrophoresis and expressed as a percentage of normal--increased slightly (median 10%, range -43 to 145, P = 0.009). In group 2, vWF increased in all patients (median 80%, range 14 to 206 [corrected], P = 0.0002 vs. baseline and group 1). In group 3, vWF decreased (median -19%, range -44 to -18). After correction for possible confounders, i.e., age, varying duration of follow-up, and initial level of vWF, the difference in vWF change between groups 1 and 2 remained significant (P = 0.009). Poor glycemic control at baseline, estimated by glycosylated hemoglobin, was a significant predictor of increases in vWF in both group 1 and groups 1 and 2 combined.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:von Willebrand factor and development of diabetic nephropathy in IDDM. 190 50

Progression of diabetic nephropathy is now associated with intrarenal hemodynamic disorders (renal hyperperfusion, hyperfiltration, intraglomerular hypertension). The cause of these disorders is unclear. It is supposed that the relaxation factor which is produced by the vascular endothelium (endothelial relaxation factor-ERF) and an endogenous nitrogen oxide (NO) can cause the above intrarenal hemodynamic alterations in diabetes mellitus. The production of ERF/NO in 35 patients with insulin-dependent diabetes mellitus who had varying severities of diabetic nephropathies were examined. These included the following groups: 1) patients without diabetic nephropathy (n = 9); 2) those with incipient diabetes mellitus (n = 12), 3) those with severe diabetes mellitus (n = 14). From groups 1 and 2, 5 patients with hyperfiltration were identified, their glomerular filtration rate were more than 140 ml/ml. The ability of the cells to produce ERF/NO was indirectly estimated, by determining the levels of human platelet guanylate cyclase in the presence of L-arginine, a NO precursor, the accumulation of cGMP in the cells and plasma. When L-arginine was present, the activity of guanylate cyclase was virtually unchanged in Group 1, but it was substantially increased in Groups 2 and 3, by reaching its peak in patients with hyperfiltration (Group 4). The platelet and plasma levels of cGMP corresponded to the enhancement of guanylate cyclase activity in the presence of L-arginine and increased as diabetic nephropathy progressed. Thus, it is suggested that there is ERF/NO hyperproduction in patients at a high risk for diabetic nephropathy (those having hyperfiltration). ERF/NO is likely to promote the dilation of glomerular arterioles, which results in the development of hyperfiltration and intraglomerular hypertension, causing diabetic nephropathy progression.
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PMID:[Endothelial relaxation factor in the development of diabetic nephropathy]. 762 82

The prevalence of hypertension in diabetes is significantly higher than in non-diabetics, perhaps twice as common. The excess is related to diabetic nephropathy, mainly in type 1 diabetes, to obesity, mainly in type 2 diabetes, but also to increased sympathetic activity. Furthermore, the increased prevalence of hypertension may relate to insulin resistance and its sequelae. Insulin resistance leads to hyperinsulinemia, relates to increased LDL and reduced HDL levels, causes the development of impaired glucose tolerance and type 2 diabetes and might also be causally related to the onset of hypertension. Syndrome X has relevant therapeutic implications in the management of hypertension. Hypertension is a major risk factor for large vessel disease in diabetics and also a risk factor for microangiopathy, particularly nephropathy. The incidence of atherosclerotic disease is dramatically increased in both type 1 and type 2 diabetics and is the major cause of morbidity and premature death mainly in patients with raised urinary albumin excretion. Thus, diabetics show a two-fold increased risk of coronary heart disease, 2-6 fold increased risk of stroke and a several-fold increased risk of peripheral vessel disease. Some evidence suggests that hypertension may be a risk factor for retinopathy, particularly its progression, but surely hypertension is a significant risk factor for nephropathy, accelerating its progression and perhaps even causing the onset of the glomerulopathy. The mechanisms by which hypertension might contribute to the evolution of both large vessel as well as small vessel disease is still unknown, although increased capillary leakage and vascular endothelium alterations might be important factors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Hypertension and diabetes]. 856 58

To evaluate the secretion of vasoactive factors in vascular endothelium of patients with non-insulin-dependent diabetes mellitus (NIDDM) the authors examined 31 NIDDM patients. Of them, 18 had no signs of renal involvement, 13 patients showed apparent diabetic nephropathy (DN). In the former patients the blood contained much greater content of vasodilating factor prostacyclin than of vasoconstricting factor endothelin-1 (ET-1) and thromboxan A2 (TxA2). In diabetic nephropathy the balance of vasoactive factors shifted to predominance of vasoconstrictors ET-1 and TxA2. Such rearrangement of vasoactive factors to higher quantities of vasoconstrictors in diabetes mellitus may initiate or promote progression of diabetic nephropathy with resultant spasm of afferent glomerular vessels, reduced glomerular filtration and renal blood flow rates, arterial hypertension, increased thrombogenesis. Thus, elevated levels of ET-1 and TxA2 in diabetics and their rise with progression of diabetic nephropathy are likely to act as pathogenetic factors underlying onset and progression of nephroangiopathy.
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PMID:[Vasoactive factors of the vascular endothelium in patients with non-insulin-dependent diabetes mellitus and kidney involvement]. 877 84

Diabetic nephropathy is preceded by 'hyperfiltration' mediated by dilatation of the afferent arterioles to the glomeruli by means of IGF-1, prostaglandins, bradykinin, nitric oxide and atrial natriuretic peptide, together with constriction of the efferent arterioles by local thromboxane A2. Raised glomerular intracapillary pressures might then contribute to glomerulosclerosis, but in any case there is permeability of the vascular endothelium. AGEPs and lipid peroxides can explain this. AGEPs, or simply intermittently high levels of glucose, also account for synthesis of extracellular matrix proteins that lead to thickening of the basement membrane and glomerulosclerosis. Another glucose product, glucosamine-6-phosphate, is formed when there is hexosamine flux along with insulin resistance in tissues, and is implicated in glomerulosclerosis, since it also stimulates TGF-beta transcription. In seeking to explain proteinuria, depletion of heparan sulphates from the endothelial cells and GBM is now established as a principal cause. In addition to a high glucose reducing the synthesis of heparan sulphates, it has now been shown that high glucose may depress the synthesis of heparin sulphate proteoglycan.
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PMID:How does hyperglycaemia predispose to diabetic nephropathy? 930 34

Functional impairment of the vascular endothelium is an early event in the development of atherosclerosis, and soluble adhesion molecules in plasma are regarded as an indicator of the endothelial damage in diabetes mellitus. We compared the soluble vascular adhesion molecule levels in the patients with diabetic nephropathy in concerning with plasma 7-ketocholesterol levels, which is major cholesterol auto-oxidation products. Average value of plasma VCAM-1 in 31 patients with type 2 diabetes mellitus was 297.6+/-10.2 ng/ml (mean+/-SE), and the value was significantly higher than that in 8 age-matched healthy controls (231.9+/-15.0 ng/ml). Among the 31 diabetic patients, the group with macroalbuminuria (n = 8) had the higher levels of plasma VCAM-1 (349.5+/-26.0 ng/ml) than the levels in the group with normoalbuminuria (n=15; 280.6+/-12.3 ng/ml). The levels of plasma 7-ketocholesterol in diabetes (26.9+/-1.5 ng/ml) or the patients with macroalbuminuria (31.4+/-3.3 ng/ml) were significantly higher than the control (22.5+/-1.8 ng/ml). The level of soluble VCAM-1 showed significant correlation between the values of 7-ketocholesterol (r=0.42, p=0.024), TC (r=0.42, p=0.014) and LDL-C (r=0.38, p=0.044). However no correlation was demonstrated with HbA1c nor creatinine level. We conclude that soluble VCAM-1 in plasma may be an indicator of oxidative stress and vascular injury in diabetic nephropathy.
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PMID:Plasma levels of soluble vascular adhesion molecule-1 and cholesterol oxidation product in type 2 diabetic patients with nephropathy. 1168 11

Macro- and microvascular disease are the most common causes of morbidity and mortality in patients with diabetes mellitus. Diabetic cardiovascular dysfunction represents a problem of great clinical importance underlying the development of various severe complications including retinopathy, nephropathy, neuropathy and increase the risk of stroke, hypertension and myocardial infarction. Hyperglycemic episodes, which complicate even well-controlled cases of diabetes, are closely associated with increased oxidative and nitrosative stress, which can trigger the development of diabetic complications. Hyperglycemia stimulates the production of advanced glycosylated end products, activates protein kinase C, and enhances the polyol pathway leading to increased superoxide anion formation. Superoxide anion interacts with nitric oxide, forming the potent cytotoxin peroxynitrite, which attacks various biomolecules in the vascular endothelium, vascular smooth muscle and myocardium, leading to cardiovascular dysfunction. The pathogenetic role of nitrosative stress and peroxynitrite, and downstream mechanisms including poly(ADP-ribose) polymerase (PARP) activation, is not limited to the diabetes-induced cardiovascular dysfunction, but also contributes to the development and progression of diabetic nephropathy, retinopathy and neuropathy. Accordingly, neutralization of peroxynitrite or pharmacological inhibition of PARP is a promising new approach in the therapy and prevention of diabetic complications. This review focuses on the role of nitrosative stress and downstream mechanisms including activation of PARP in diabetic complications and on novel emerging therapeutical strategies offered by neutralization of peroxynitrite and inhibition of PARP.
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PMID:Role of nitrosative stress and peroxynitrite in the pathogenesis of diabetic complications. Emerging new therapeutical strategies. 1572 18

The subjects of the study were 30 patients with type II diabetes and arterial hypertension. The purpose of the study was comparative clinical characterization of type II diabetes patients with and without microalbuminuria (MAU), and evaluation of effects of 16-week therapy aimed at stimulation of NO synthesis by vascular endothelium, on the pathogenesis of diabetic nephropathy. The results show that patients with MAU, unlike those without it, are characterized by longer course of diabetes, more pronounced lipid exchange disorder, more variable arterial pressure, higher pressure load index, elevated activity of lipid peroxidation (LP) processes, prominent disorder of NO-producing endothelial function. After 16 weeks of treatment, both groups demonstrated significant increase of NO basal secretion, prominent reduction of arterial hypertension, significant improvement of important carbohydrate and lipid exchange parameters, reduction of LP activity, and thus reduction of MAU. The listed changes were more significant in patients with MAU.
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PMID:[NO synthesis in the vascular endothelium of patients with type II diabetes]. 1621 68

In many forms of experimental kidney diseases, renal VEGF is low, and administering VEGF can be shown to be protective. A paradox occurs in diabetes, in which renal VEGF levels are high and a deleterious effect of VEGF on kidney disease has been shown. We have hypothesized that endothelial dysfunction induced by hyperglycemia or other factors may underlie the pathogenic mechanisms of a high VEGF state. VEGF normally stimulates endothelial nitric oxide (NO) release and acts in concert with elevated NO levels as a trophic factor for vascular endothelium. The increased NO derived from the endothelial cell acts as an inhibitory factor that prevents excess endothelial cell proliferation, vascular smooth muscle cell proliferation, and macrophage infiltration. In the setting where NO bioavailability is reduced in diabetes, high levels of VEGF lead to excessive endothelial cell proliferation, stimulation of macrophage chemotaxis, and vascular smooth muscle cell activation. Consistent with this hypothesis is our recent observation that diabetes induced in endothelial NO-deficient mice results in clinical and histological features identical to human diabetic nephropathy. The discovery of the key role for impaired endothelial NO bioavailability in the stimulation of VEGF and VEGF-dependent disease may provide key insights into not only the pathogenesis of diabetic nephropathy but also the utility and hazard of administering VEGF as a treatment for kidney disease.
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PMID:Uncoupling of the VEGF-endothelial nitric oxide axis in diabetic nephropathy: an explanation for the paradoxical effects of VEGF in renal disease. 1754 2

Diabetic nephropathy is the leading cause of chronic renal failure. Myofibroblasts play a major role in the synthesis and secretion of extracellular matrix in diabetic renal fibrosis. Increasing evidence suggests that endothelial cells may undergo endothelial-myofibroblast transition under physiological and pathophysiological circumstances. Therefore, this study investigates whether endothelial-myofibroblast transition occurs and contributes to the development of diabetic renal interstitial fibrosis. Diabetes was induced by administration of streptozotocin to Tie2-Cre;LoxP-EGFP mice, an endothelial lineage-traceable mouse line generated by crossbreeding B6.Cg-Tg(Tek-cre)12F1v/J mice with B6.Cg-Tg(ACTB-Bgeo/GFP)21Lbe/J mice. The endothelial-myofibroblast transition was also studied in MMECs (a mouse pancreatic microvascular endothelial cell line) and primary cultures of CD31+/EYFP- (enhanced yellow fluorescent protein) endothelial cells isolated from adult normal alpha-smooth muscle actin promoter-driven-EYFP (alpha-SMA/EYFP) mouse kidneys. Confocal microscopy demonstrated that 10.4 +/- 4.2 and 23.5 +/- 7.4% of renal interstitial myofibroblasts (alpha-SMA+) in 1- and 6-month streptozotocin-induced diabetic kidneys were of endothelial origin (EGFP+/alpha-SMA+ cells), compared with just 0.2 +/- 0.1% of myofibroblasts in vehicle-treated Tie2-Cre;LoxP-EGFP mice (P < 0.01). Confocal microscopy and real-time PCR showed that transforming growth factor (TGF)-beta1 induced de novo expression of alpha-SMA and loss of expression of VE-cadherin and CD31 in MMECs and primary cultures of renal endothelial cells in a time- and dose-dependent fashion. These findings demonstrate that the endothelial-myofibroblast transition occurs and contributes to the early development and progression of diabetic renal interstitial fibrosis and suggest that the endothelial-myofibroblast transition may be a therapeutic target.
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PMID:Endothelial-myofibroblast transition contributes to the early development of diabetic renal interstitial fibrosis in streptozotocin-induced diabetic mice. 1972 86


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