The meaning of serum levels of advanced glycosylation end products in diabetic nephropathy.
ABSTRACT It has been reported that advanced glycosylation end products (AGEs) play an important role in the development of diabetic complications. To evaluate the relationship between serum AGEs and diabetic nephropathy, we measured serum AGE levels in diabetic patients with normoalbuminuria (N), microalbuminuria (M), overt proteinuria (O), and hemodialysis (HD), non diabetic patients with nephropathy, and age-matched control subjects using the enzyme-linked immunosorbent assay (ELISA). Urine AGE levels were also measured in these subjects except group HD. Serum AGE levels in diabetic patients were not significantly higher than those in the normal subjects. When we compared serum AGE levels among various stages of diabetic nephropathy, groups O and HD had significantly higher serum AGE levels than the other groups. Serum AGE levels in group HD were almost 6-fold higher than those in groups N and M. In contrast, there were no significant differences in urinary AGE levels among any diabetic groups. As for the variables that determine serum AGE levels in diabetic patients, there was no significant correlation between serum AGEs and fasting blood glucose, hemoglobin A1c (HbA1c), or duration of diabetes. In contrast, serum AGEs showed a strong correlation with serum creatinine and an inverse correlation with creatinine clearance. To evaluate the relationship between serum AGEs and oxidative stress in diabetic nephropathy, urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and serum malondialdehyde (MDA), which are biological markers of total oxidative stress in vivo, were also examined. Both urinary 8-OHdG and serum MDA levels were significantly higher in diabetic patients with proteinuria versus those without proteinuria. However, there was no significant correlation between serum AGEs and urinary 8-OHdG or serum MDA levels in diabetic patients. These results suggest that the accumulation of serum AGEs in diabetic nephropathy may be mainly due to decreased removal in the kidney rather than increased production by high glucose levels or oxidative stress.
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ABSTRACT: The activation of platelet-derived growth factor receptor-β (PDGFR-β) signalling is increased in the glomeruli and tubules of diabetic animals. In this study, we examined the role of PDGFR-β signalling during the development of diabetic nephropathy. We recently generated pancreatic beta cell-specific Ca(2+)/calmodulin-dependent protein kinase IIα (Thr286Asp) transgenic mice (CaMKIIα mice), which show very high plasma glucose levels up to 55.5 mmol/l and exhibit the features of diabetic nephropathy. These mice were crossed with conditional knockout mice in which Pdgfr-β (also known as Pdgfrb) was deleted postnatally. The effect of the deletion of the Pdgfr-β gene on diabetic nephropathy in CaMKIIα mice was evaluated at 10 and 16 weeks of age. The plasma glucose concentrations and HbA(1c) levels were elevated in the CaMKIIα mice from 4 weeks of age. Variables indicative of diabetic nephropathy, such as an increased urinary albumin/creatinine ratio, kidney weight/body weight ratio and mesangial area/glomerular area ratio, were observed at 16 weeks of age. The postnatal deletion of the Pdgfr-β gene significantly decreased the urinary albumin/creatinine ratio and mesangial area/glomerular area ratio without affecting the plasma glucose concentration. Furthermore, the increased oxidative stress in the kidneys of the CaMKIIα mice as shown by the increased urinary 8-hydroxydeoxyguanosine (8-OHdG) excretion and the increased expression of NAD(P)H oxidase 4 (NOX4), glutathione peroxidase 1 (GPX1) and manganese superoxide dismutase (MnSOD) was decreased by Pdgfr-β gene deletion. The activation of PDGFR-β signalling contributes to the progress of diabetic nephropathy, with an increase in oxidative stress and mesangial expansion in CaMKIIα mice.Diabetologia 08/2011; 54(11):2953-62. · 6.49 Impact Factor
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ABSTRACT: Oxidatively damaged DNA is implicated in various diseases, including neurodegenerative disorders, cancer, diabetes, cardiovascular and inflammatory diseases as well as aging. Several methods have been developed to detect oxidatively damaged DNA. They include chromatographic techniques, the Comet assay, (32)P-postlabelling and immunochemical methods that use antibodies to detect oxidized lesions. In this review, we discuss the detection of 8-oxo-7,8-dihydro-29-deoxyguanosine (8-oxodG), the most abundant oxidized nucleoside. This lesion is frequently used as a marker of exposure to oxidants, including environmental pollutants, as well as a potential marker of disease progression. We concentrate on studies published between the years 2000 and 2011 that used enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry to detect 8-oxodG in humans, laboratory animals and in cell lines. Oxidative damage observed in these organisms resulted from disease, exposure to environmental pollutants or from in vitro treatment with various chemical and physical factors.Free radical research 11/2011; 46(4):492-522. · 2.22 Impact Factor
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ABSTRACT: Diabetes mellitus and its complications are becoming one of the most important health problems in the world. Diabetic nephropathy is now the main cause of end-stage renal disease. The mechanisms leading to the development and progression of renal injury are not well known. Therefore, it is very important to find new pathogenic pathways to provide opportunities for early diagnosis and targets for novel treatments. At the present time, we know that activation of innate immunity with development of a chronic low grade inflammatory response is a recognized factor in the pathogenesis of diabetic nephropathy. Numerous experimental and clinical studies have shown the participation of different inflammatory molecules and pathways in the pathophysiology of this complication.World journal of diabetes. 01/2012; 3(1):7-18.