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

Oxygen free radicals (OFRs) have been suggested to be a contributory factor in complications of diabetes mellitus. In the present study, we investigated the lipid peroxide level measured as thiobarbituric acid reactive substances (TBARS) and activities of antioxidant enzymes viz., [superoxide dismutase (SOD), catalase (CAT) and glutathione-peroxidase (GSH-Px)] in the kidney of streptozotocin induced diabetic rats at various stages of development of diabetes. Sprague Dawley rats were divided into two groups: group I, control (n = 42) and group II, diabetic (n = 42). Each group was further subdivided into seven groups each consisting of six rats. Rats in subgroups were studied at weekly intervals (0 to 6 weeks). Blood glucose levels were estimated at the time of sacrifice. TBARS levels and activity of antioxidant enzymes were measured in kidney. The levels of TBARS in the diabetic group increased initially, dropped to baseline level after 2 weeks and then progressively increased at 5th and 6th week (p < 0.05). There was an increase in catalase activity at first week after that it decreased as compared to control group. However, GSH-Px activity in the diabetic group increased after 1 week and then remained at the same level except a small drop in the 2nd week. Total SOD and CuZn-SOD activity increased significantly in diabetic kidney as compared to controls at all time intervals, while Mn-SOD activity showed no change. The present findings suggest that oxidative stress accompanies at early onset of diabetes mellitus and the susceptibility of the kidney to oxidative stress during the early stages may be an important factor in the development of diabetic nephropathy.
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PMID:Antioxidant defense system in diabetic kidney: a time course study. 904 69

The aim of this study was to analyse the effect of angiotensin convertase inhibitor, enalapril (ENA), and angiotensin AT-1 receptor antagonist, losartan potassium (LP), on lipid peroxidation and activities of Cu,Zn-superoxide dismutase, catalase and glutathione peroxidase in kidneys of streptozotocin (STZ)-induced diabetic rats after 6 and 12 weeks of treatment. STZ-induced body weight changes and blood glucose concentration were not affected by either ENA or LP but both drugs significantly decreased cholesterol and triglyceride concentrations elevated in diabetic rats, inhibited kidney weight gain, and decreased albuminuria. Kidneys of STZ-diabetic rats had increased malondialdehyde content and decreased activities of antioxidant enzymes (Cu,Zn-superoxide dismutase, catalase and glutathione peroxidase). Both ENA and LP decreased lipid peroxidation and augmented the activities of antioxidant enzymes studied in the kidneys of diabetic rats. These results confirm the role of oxidative stress in the development of diabetic nephropathy already at early stages of the development of diabetes and point to the possible antioxidative mechanism of the nephroprotective action of ENA and LP.
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PMID:Effect of angiotensin convertase inhibitors and AT1 angiotensin receptor antagonists on the development of oxidative stress in the kidney of diabetic rats. 1050 93

Both reactive oxygen species (ROS) and endothelin-1 (ET- 1) have been implicated in the pathophysiology of diabetic nephropathy. The interrelationship between them, however, has not been documented in this disease. To determine whether ROS regulates ET-1 production in diabetic kidneys, we examined the in vitro and in vivo effects of ROS donors and scavengers on ET-1 production of diabetic rat glomeruli. For in vitro study, the glomeruli were isolated with a sieving method from streptozotocin-induced diabetic rats and killed at 1 week, 1 month, and 3 months, respectively. Superoxide was measured by a spectrophotometer, and ET-1 was measured by radioimmunoassay. The results demonstrated that the basal production levels of superoxide and ET-1 were higher in diabetic glomeruli than in normal glomeruli in vitro. There was a positive correlation between the production of superoxide and ET-1 in diabetic glomeruli. The basal ET-1 production was markedly attenuated by ROS scavengers including superoxide dismutase, catalase, dimethyl sulfoxide, and deferoxamine in diabetic glomeruli. Exogenous ROS generated by xanthine/xanthine oxidase significantly enhanced ET-1 generation by both diabetic and normal glomeruli. A high glucose concentration (500 mg/dL) in vitro increased ET-1 production by normal glomeruli but not diabetic glomeruli, and insulin partly suppressed ET- 1 production by diabetic glomeruli. The in vivo study demonstrated that when diabetic rats were injected daily with superoxide dismutase or catalase after diabetes was induced, the basal production of ET-1 was markedly attenuated after 1 week and 1 month, respectively. These results indicate that exogenously or endogenously derived ROS can enhance ET-1 production by diabetic rat glomeruli and that ROS scavengers suppress ET- 1 production both in vitro and in vivo. The effects of ROS on ET-1 production of diabetic glomeruli may be partly caused by the effect of hyperglycemia or insulin deficiency.
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PMID:Reactive oxygen species enhances endothelin-1 production of diabetic rat glomeruli in vitro and in vivo. 1077 44

There is an individual susceptibility to diabetic nephropathy, and oxidative stress is believed to play an important role in the pathogenesis of diabetic complications. Active oxygen species induce antioxidant enzyme expression in tissues, an effect considered to be a defensive mechanism. To test whether altered intracellular antioxidant enzyme production might explain the predisposition to diabetic nephropathy, we studied the effect of long-term (12 weeks) exposure to normal (5 mmol/l) or high (22 mmol/l) glucose concentrations on fibroblast antioxidant enzyme gene expression and protein activity in type 1 diabetic patients with and without nephropathy, nondiabetic nephropathic patients, and nondiabetic control subjects. Under conditions of normal glucose concentration in the culture media, CuZnSuperoxide-dismutase, MnSuperoxide-dismutase, catalase, and glutathione-peroxidase activity and mRNA expression were not different among the four groups. Under high-glucose conditions, CuZnSuperoxide-dismutase mRNA and activity increased similarly in all groups (P < 0.001 vs. basal), whereas MnSuperoxide-dismutase did not change. In contrast, catalase mRNA and activity as well as glutathione-peroxidase mRNA and activity increased in fibroblasts from type 1 diabetic patients without nephropathy (P < 0.001), in fibroblasts from nondiabetic nephropathic patients (P < 0.001), and in fibroblasts from nondiabetic control subjects (P < 0.001), but not in fibroblasts from type 1 diabetic patients with nephropathy. Exposure to high glucose concentrations significantly increased lipid peroxidation in cells, higher levels being found in cells from diabetic patients with nephropathy (P < 0.001). These data, while confirming that exposure to high glucose concentrations induces an antioxidant defense in skin fibroblasts from normal subjects, demonstrate a failure of this defensive mechanism in cells from type 1 diabetic patients with nephropathy, whereas skin fibroblasts from diabetic patients without complications or from nondiabetic nephropathic patients have an intact antioxidant response to glucose-induced oxidative stress.
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PMID:Defective intracellular antioxidant enzyme production in type 1 diabetic patients with nephropathy. 1111 22

Diabetic nephropathy is characterised by an increase in glomerular and tubular fibrosis that compromises kidney function. The transforming growth factor-betas (TGF-betas) have been shown to play a major role in fibrosis and we have shown that TGF-beta2, in particular, increases co-ordinately with fibrogenesis in the diabetic kidney. The aim of this study was to investigate the changes in expression of extracellular matrix molecules in the diabetic kidney, with and without systemic administration of a recombinant human monoclonal antibody to TGF-beta2. Streptozotocin-induced diabetic rats were split into two groups. The first were treated with 5 mg/kg irrelevant control IgG4 (placebo) and the second treated with 5 mg/kg isoform-specific recombinant monoclonal anti-TGF-beta2 IgG4 (termed CAT-152) systemically every second day for 14 days. A further group of six non-diabetic rats was also used as a control. Various biological parameters were measured daily throughout the experimental period, and on termination of the experiment at 14 days Western blotting was performed on kidney cortices for procollagen-I C-propeptide, which is an indicator of the rate of collagen-I synthesis within the kidney. In the placebo-treated diabetic rats, blood glucose, food consumption, urinary albumin excretion (UAE) and kidney weights were all significantly higher than in the non-diabetic group (P<0.05, n=24, by ANOVA). In the anti-TGF-beta2-treated diabetic rats, kidney weights and UAE levels were decreased when compared with those in placebo-treated diabetics. Western blotting for the procollagen-I C-propeptide in kidney cortices showed a significant increase in levels in placebo-treated diabetic rats compared with non-diabetic controls over the 14 day diabetic period, indicating initiation of fibrogenesis. By contrast, in anti-TGF-beta2-treated diabetic rats, levels of the propeptide remained at non-diabetic levels. In summary, a significant suppression of kidney fibrosis was seen in anti-TGF-beta2-treated diabetic rats, compared with placebo-treated diabetic rats. We conclude that systemic delivery of CAT-152, a neutralising anti-TGF-beta2 antibody, during the acute stages of diabetic nephropathy reduces the rate of pathogenic fibrosis in the kidney.
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PMID:Transforming growth factor-beta2 antibody attenuates fibrosis in the experimental diabetic rat kidney. 1152 45

Diabetes is associated with a significant increase in thiobarbituric acid reactive substances (TBARS) which are considered as an index of endogenous lipid peroxidation. The human body has a complex antioxidant defense system that prevents the initiation of free radical chain reactions. We measured plasma TBARS levels, superoxide dismutase (SOD) and catalase (CAT) activities and compared their relation to the metabolic control of diabetes and diabetic microangiopathy. Sixty-four patients (19 men), aged 52.35+/-9.31 years with type 2 diabetes mellitus were included in the study. Thirty-six healthy subjects (12 men), aged 51.02+/-7.01 years formed the control group. TBARS levels and SOD activity were elevated in the diabetic group when compared with the control group ( p<0.001 and p<0.00001, respectively). However CAT activity was significantly decreased in the diabetic group when compared with the control group ( p<0.00001). Patients with diabetic nephropathy and retinopathy, but not neuropathy, had elevated TBARS levels but there was no statistically significant difference when compared with diabetic patients without microangiopathy ( p>0.05). There was a positive correlation between plasma TBARS levels and SOD activity (r=0.770, p=0.0001) and a negative correlation between plasma TBARS levels and CAT activity (r=0.482, p=0.0001). There was also a negative correlation between SOD and CAT activities (r=-0.609, p=0.0001). We found significantly elevated TBARS levels in diabetic patients. We did not observe any correlation between TBARS levels and blood glucose and HbA(1c) levels. Elevated TBARS levels and SOD activity and decreased CAT activity may be due to a compensation mechanism of the body.
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PMID:Plasma lipid peroxidation products and antioxidant enzyme activities in patients with type 2 diabetes mellitus. 1235 95

Oxidative stress is implicated in the pathogenesis of diabetic nephropathy. The attempts to identify early markers of diabetes-induced renal oxidative injury resulted in contradictory findings. We characterized early oxidative stress in renal cortex of diabetic rats, and evaluated whether it can be prevented by the potent antioxidant, DL-alpha-lipoic acid. The experiments were performed on control rats and streptozotocin-diabetic rats treated with/without DL-alpha-lipoic acid (100 mg/kg i.p., for 3 weeks from induction of diabetes). Malondialdehyde plus 4-hydroxyalkenal concentration was increased in diabetic rats vs. controls (p <.01) and this increase was partially prevented by DL-alpha-lipoic acid. F(2) isoprostane concentrations (measured by GCMS) expressed per either mg protein or arachidonic acid content were not different in control and diabetic rats but were decreased several-fold with DL-alpha-lipoic acid treatment. Both GSH and ascorbate (AA) levels were decreased and GSSG/GSH and dehydroascorbate/AA ratios increased in diabetic rats vs. controls (p <.01 for all comparisons), and these changes were completely or partially (AA) prevented by DL-alpha-lipoic acid. Superoxide dismutase, glutathione peroxidase, glutathione reductase, glutathione transferase, and NADH oxidase, but not catalase, were upregulated in diabetic rats vs. controls, and these activities, except glutathione peroxidase, were decreased by DL-alpha-lipoic acid. In conclusion, enhanced oxidative stress is present in rat renal cortex in early diabetes, and is prevented by DL-alpha-lipoic acid.
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PMID:Early oxidative stress in the diabetic kidney: effect of DL-alpha-lipoic acid. 1252

Renin-angiotensin system (RAS) inhibitors are effective in reducing renal disease progression in early diabetic nephropathy, but they provide imperfect protection at a later stage. Due to the pivotal role of transforming growth factor-beta (TGF-beta) in the pathogenesis of diabetic kidney disease, this study tested the effect of simultaneously interrupting TGF-beta and angiotensin II on disease progression in diabetic rats with overt nephropathy. Diabetes was induced by streptozotocin injection in uninephrectomized rats. Diabetic rats received murine (1D11) or human (CAT-192) anti-TGF-beta monoclonal antibodies alone or in combination with lisinopril, 13C4 irrelevant murine antibody, saline or lisinopril from month 4 (when animals had proteinuria) to month 8. Normal animals served as controls. Systolic BP increase was controlled by single treatments and even more by the combined therapies. 1D11 and lisinopril kept proteinuria at levels numerically lower than irrelevant antibody and saline, while CAT-192 was ineffective. The addition of either TGF-beta antibody to lisinopril normalized proteinuria. Consistent results were obtained for glomerulosclerosis and tubular damage, which were abrogated by the combined therapy. Interstitial volume expansion and infiltration of lymphocytes/macrophages were limited by 1D11 and lisinopril and further reduced by their combination. The increase of type III collagen in the renal interstitium was partially attenuated by 1D11 and lisinopril while normalized by their combination. It is concluded that anti-TGF-beta antibody when added to a background of chronic angiotensin-converting enzyme (ACE) inhibition fully arrests proteinuria and renal injury of overt diabetic nephropathy, providing a novel route to therapy and remission of disease for diabetic patients who do not respond to RAS inhibition.
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PMID:Add-on anti-TGF-beta antibody to ACE inhibitor arrests progressive diabetic nephropathy in the rat. 1281 41

TGF-beta (transforming growth factor-beta) is implicated in the pathogenesis of diabetic nephropathy. We previously demonstrated that up-regulation of type II TGF-beta receptor (TbetaRII) induced by high glucose might contribute to distal tubular hypertrophy [Yang, Guh, Yang, Lai, Tsai, Hung, Chang and Chuang (1998) J. Am. Soc. Nephrol. 9, 182-193]. We have elucidated the mechanism by using cultured Madin-Darby canine kidney cells. Enhancer assay and electrophoretic-mobility-shift assay were used to estimate the involvement of transcription factors. Western blotting and an in vitro kinase assay were used to evaluate the level and activity of protein kinase. We showed that glucose (100-900 mg/dl) induced an increase in mRNA level and promoter activity of TbetaRII (note: 'mg/dl' are the units commonly used in diabetes studies). The promoter region -209 to -177 appeared to contribute to positive transactivation of TbetaRII promoter by comparing five TbetaRII-promoter-CAT (chloramphenicol acetyl-transferase) plasmids. Moreover, the transcription factor AP-1 (activator protein 1) was significantly activated and specifically binds to TbetaRII promoter (-209 to -177). More importantly, we found that atypical PKC iota might be pivotal for high glucose-induced increase in both AP-1 binding and TbetaRII promoter activity. First, high glucose induced cytosolic translocation, activation and autophosphorylation of PKC iota. Secondly, antisense PKC iota expression plasmids attenuated high-glucose-induced increase in AP-1 binding and TbetaRII promoter activity; moreover, sense PKC iota expression plasmids enhanced these instead. Finally, we showed that antisense PKC iota expression plasmids might partly attenuate a high-glucose/TGF-beta1-induced increase in fibronectin. We conclude that PKC iota might mediate high-glucose-induced increase in TbetaRII promoter activity. In addition, antisense PKC iota expression plasmid effectively suppressed up-regulation of TbetaRII and fibronectin in hyperglycaemic distal-tubule cells.
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PMID:Regulation of type II transforming-growth-factor-beta receptors by protein kinase C iota. 1284 49

Numerous reports have demonstrated that oxidative stress induced by diabetes plays an important role in the development and progression of diabetic vascular complications including nephropathy. Indeed, there is emerging evidence that the formation of reactive oxygen species (ROS) is a direct consequence of hyperglycemia. Biomarkers for oxidative damage to DNA, lipids, and proteins are also supporting the concept of increased oxidative stress in diabetes and diabetic nephropathy. However, there is an unanswered question: When does oxidative stress as a pathogenetic event occur in the process of diabetic nephropathy? To answer this question, glomerular ROS was imaged with the use of 2', 7'-dichlorofluorescein diacetate (DCFH-DA). The image of DCF fluorescence was strong in glomeruli from diabetic rats as compared with that of glomeruli from nondiabetic control rats. mRNA expression of antioxidant enzymes such as catalase, glutathione peroxidase, Cu/Zn superoxide dismutase, and heme oxygenase-1 (HO-1) was also determined because oxidative stress definitely refers to the situation of an imbalance between the production of ROS and antioxidant defense. The mRNA expression of catalase, glutathione peroxidase, and Cu/Zn superoxide dismutase 2 wk after the induction of diabetes was not significantly different from that in control rats. Alternatively, mRNA and protein expression of HO-1 was strongly induced by 16-fold in diabetic glomeruli after the induction of diabetes. Antioxidant treatment with either vitamin E or probucol almost completely normalized HO-1 overexpression in diabetic glomeruli, supporting the existence of oxidative stress in the glomeruli of early diabetes. Furthermore, It has reported that antioxidant treatment with vitamin E, probucol, alpha-lipoic acid, or taurine normalized diabetes-induced not only renal dysfunction such as albuminuria and glomerular hypertension but also glomerular pathologies. In summary, oxidative stress by diabetes could play a crucial role in the development and progression of diabetic nephropathy, and antioxidant treatment could be a potential therapeutic procedure for diabetic nephropathy.
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PMID:Effects of antioxidants in diabetes-induced oxidative stress in the glomeruli of diabetic rats. 1287 41


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