Histological Localization of Advanced Glycosylation End Products in the Progression of Diabetic Nephropathy

Imai, Naofumi; Nishi, S; Suzuki, Yuichi; Karasawa, R; Ueno, Mitsuhiro; Shimada, Hideaki; Kawashima, Shinji; Nakamaru, Tsukasa; Miyakawa, Yoshikazu; Araki, Nobuhito; Horiuchi, Seikoh; Gejyo, Fumitake; Arakawa, Masaaki

doi:10.1159/000190163

Cited by 24 publications

(13 citation statements)

References 19 publications

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“…Although several AGE structures have been reported, our group (1) and Reddy et al (2) independently demonstrated that N ε -(carboxymethyl)lysine (CML) is a major antigenic AGE structure. CML concentration, adjusted for age and duration of diabetes, is also increased in patients who have diabetes with complications, including nephropathy (3)(4)(5), retinopathy (6), and atherosclerosis (7)(8)(9). CML is also recognized by receptor for AGE (RAGE), and CML-RAGE interaction activates cell signaling pathways such as NF-B and enhances the expression of vascular cell adhesion molecule-1 in human umbilical vein endothelial cells (10).…”

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confidence: 99%

Peroxynitrite Induces Formation ofNε-(Carboxymethyl)Lysine by the Cleavage of Amadori Product and Generation of Glucosone and Glyoxal From Glucose

et al. 2002

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Accumulation of advanced glycation end products (AGEs) on tissue proteins increases with pathogenesis of diabetic complications and atherosclerosis. Here we examined the effect of peroxynitrite (ONOO ؊ ) on the formation of N -(carboxymethyl)lysine (CML), a major AGE-structure. When glycated human serum albumin (HSA; Amadori-modified protein) was incubated with ONOO ؊ , CML formation was detected by both enzymelinked immunosorbent assay and high-performance liquid chromatography (HPLC) and increased with increasing ONOO ؊ concentrations. CML was also formed when glucose, preincubated with ONOO ؊ , was incubated with HSA but was completely inhibited by aminoguanidine, a trapping reagent for ␣-oxoaldehydes. For identifying the aldehydes that contributed to ONOO ؊ -induced CML formation, glucose was incubated with ONOO ؊ in the presence of 2,3-diaminonaphthalene. This experiment led to identification of glucosone and glyoxal by HPLC. Our results provide the first evidence that ONOO ؊ can induce protein modification by oxidative cleavage of the Amadori product and also by generation of reactive ␣-oxoaldehydes from glucose.

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confidence: 99%

Peroxynitrite Induces Formation ofNε-(Carboxymethyl)Lysine by the Cleavage of Amadori Product and Generation of Glucosone and Glyoxal From Glucose

et al. 2002

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“…Immunohistochemical observations in diabeticrat models have shown AGE accumulation in the glomerular extracellular matrix [19,20]. In human diabetic patients, the accumulation of AGE, in particular, CML, pentosidine and malondialdehyde in glomerular lesions, is related to disease severity and in the presence of an up-regulated receptor for AGE (RAGE) in podocytes [21,22]. The toxic effects of these AGE result from structural and functional alterations in plasma and extracellular matrix (ECM) proteins, in particular, from cross-linking of proteins and interaction of AGEs with their receptors and/or binding proteins.…”

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confidence: 99%

LR-90 a new advanced glycation endproduct inhibitor prevents progression of diabetic nephropathy in streptozotocin-diabetic rats

et al. 2003

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Aims/hypothesis. Advanced glycation and lipoxidation endproducts have been implicated in the pathogenesis of diabetic complications, including diabetic nephropathy. LR-90, a new advanced glycation endproduct inhibitor, was investigated for its effects on the development of renal disease in diabetic rats. Methods. Diabetic animals were randomly allocated into groups receiving LR-90 or vehicle (untreated). Age-and weight-matched non-diabetic rats were studied concurrently. Body weight, plasma glucose, glycated haemoglobin, urinary albumin and creatine excretions were measured serially. Kidney histopathology, AGE accumulation in cells and tissues, protein oxidation, were also examined. In vitro assays were used to assess the possible mechanism of action of LR-90. Results. LR-90 inhibited the increase in albumin and creatinine concentrations, and concentrations of circulating AGE in diabetic rats without any effect on glycaemic control. LR-90 treated-rats also showed higher body weights than untreated diabetic rats. LR-90 prevented glomerulosclerosis, tubular degeneration and collagen deposition in the kidney. AGE-induced crosslinking and fluorescence of tail collagen were reduced by LR-90 treatment. LR-90 also decreased AGE accumulation in kidney glomeruli and nitrotyrosine deposition in the renal cortex. In vitro, LR-90 was capable of reacting with reactive carbonyl compounds and was a more potent metal chelator than pyridoxamine and aminoguanidine. Conclusion/interpretation. LR-90 reduces in vivo AGE accumulation, AGE-protein cross-linking and protein oxidation, and could be beneficial in preventing the progression of diabetic nephropathy. The AGE inhibitory and therapeutic effects of LR-90 could be attributed, at least in part, to its ability to react with reactive carbonyl species and/or potent metal chelating activity that inhibits glycoxidative-AGE formation.

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“…AGEs are known for their heterogeneity, including pyrraline, pentosidine, crossline, and carboxymethyllysine. Some reports have described excessive amounts of AGEs in renal tissue specimens from diabetic patients [2, 3, 4, 5]. Carboxymethyllysine, a major chemical component of AGEs that accumulates in tissue proteins [15], is found in the expanded mesangial matrix and in the thickened glomerular basement membrane [16]in diabetic nephropathy.…”

Section: Discussionmentioning

confidence: 99%

“…AGEs have been found to accumulate in the glomeruli of diabetic patients with nephropathy [2, 3, 4, 5]. Since AGE measurement in tissue specimens is not useful in clinical practice, analysis of blood samples has been pursued.…”

Section: Introductionmentioning

confidence: 99%

Serum Levels of Advanced Glycosylation End Products in Diabetic Nephropathy

Kanauchi

Nishioka²,

Dohi³

2001

Nephron

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Background/Aims: Advanced glycosylation end products (AGEs) are important pathogenetic factors underlying diabetic complications. Recently, a highly reliable new enzyme-linked immunosorbent assay for these metabolites has been established. We used the assay to correlate AGEs in serum with renal function categories and histopathology in patients with diabetic nephropathy. Methods: Type 2 diabetic patients (n = 71) and healthy control subjects (n = 35) were studied. The diabetic subjects were divided into two groups: normal renal function and chronic renal failure not requiring dialysis. In renal biopsy specimens from 22 diabetic subjects with a normal renal function, the severity of glomerular lesions was assessed morphometrically in terms of the ratio of the area of periodic acid-Schiff stained mesangium to total glomerular area. Results: The serum AGE concentrations were higher in both undialyzed diabetic groups, especially in those with renal failure, than in the controls. The serum AGE concentrations increased with the severity of glomerular lesions (morphometric ratio under 15%, 2.85 ± 0.73 mU/ml; 15–24%, 4.01 ± 0.71 mU/ml; 25% or more, 5.12 ± 0.64 mU/ml). Conclusions: The serum AGE levels measured by the new enzyme-linked immunosorbent assay reflected the severity of glomerulopathy, and, therefore, it may be a clinically useful tool for assessing diabetic renal complications.

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Histological Localization of Advanced Glycosylation End Products in the Progression of Diabetic Nephropathy

Cited by 24 publications

References 19 publications

Peroxynitrite Induces Formation ofNε-(Carboxymethyl)Lysine by the Cleavage of Amadori Product and Generation of Glucosone and Glyoxal From Glucose

Peroxynitrite Induces Formation ofNε-(Carboxymethyl)Lysine by the Cleavage of Amadori Product and Generation of Glucosone and Glyoxal From Glucose

LR-90 a new advanced glycation endproduct inhibitor prevents progression of diabetic nephropathy in streptozotocin-diabetic rats

Serum Levels of Advanced Glycosylation End Products in Diabetic Nephropathy

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