. Advanced glycation end products (AGE) include a variety of protein adducts whose accumulation has been implicated in tissue damage associated with diabetic nephropathy (DN). It was recently demonstrated that among AGE, glycoxidation products, whose formation is closely linked to oxidation, such as carboxymethyllysine (CML) and pentosidine, accumulate in expanded mesangial matrix and nodular lesions in DN, in colocalization with malondialdehyde-lysine (MDA-lysine), a lipoxidation product, whereas pyrraline, another AGE structure whose deposition is rather independent from oxidative stress, was not found within diabetic glomeruli. Because CML, pentosidine, and MDA-lysine are all formed under oxidative stress by carbonyl amine chemistry between protein amino group and carbonyl compounds, their colocalization suggests a local oxidative stress and increased protein carbonyl modification in diabetic glomerular lesions. To address this hypothesis, human renal tissues from patients with DN or IgA nephropathy were examined with specific antibodies to characterize most, if not all, carbonyl modifications of proteins by autoxidation products of carbohydrates, lipids, and amino acids: CML (derived from carbohydrates, lipids, and amino acid), pentosidine (derived from carbohydrates), MDA-lysine (derived from lipids), 4-hydroxynonenal-protein adduct (derived from lipids), and acrolein-protein adduct (derived from lipids and amino acid). All of the protein adducts were identified in expanded mesangial matrix and nodular lesions in DN. In IgA nephropathy, another primary glomerular disease leading to end-stage renal failure, despite positive staining for MDA-lysine and 4-hydroxynonenal-protein adduct in the expanded mesangial area, CML, pentosidine, and acrolein-protein adduct immunoreactivities were only faint in glomeruli. These data suggest a broad derangement in nonenzymatic biochemistry in diabetic glomerular lesions, and implicate an increased local oxidative stress and carbonyl modification of proteins in diabetic glomerular tissue damage (“carbonyl stress”).

Immunohistochemical evidence for an increased oxidative stress and carbonyl modification of proteins in diabetic glomerular lesions.

Objective To evaluate the usefulness of renal biopsy in the overall management of patients with diabetes mellitus (DM), we examined the relationship between the clinical parameters and histopathological findings of renal biopsy samples. Methods Renal biopsy specimens were obtained from 109 type 2 diabetic patients with proteinuria. Samples were divided into the following two groups: Diabetic Nephropathy (DN) group (n=80) had typical diabetic lesions without other renal diseases, complication group (n=29) had diabetic lesions with other renal diseases. Furthermore, DN group was subdivided into two subgroups: slow progressive group (SP group, n=32), the level of serum creatinine (s-Cr) was normal at the time of renal biopsy and three years after renal biopsy, and fast progressive group (FP group, n=14), the level of s-Cr was normal at the time of renal biopsy but more than doubled three years after renal biopsy. Results The level of total protein was significantly lower and HbAlc significantly higher in the DN group than in the Complication group. However, other clinical parameters were not significantly different between the two groups. Urinary protein, systolic and diastolic blood pressure in FP group were significantly higher than in SP group. The percentage of sclerotic glomeruli, the severity of mesangial expansion, tubular injury and cell infiltration were significantly greater in FP than in SP group. Conclusions Our results indicated that a complete evaluation of renal pathology in DM could not be made by clinical parameters only, and that the progression of DN could be accurately predicted by histopathological evaluation. Therefore, this study emphasizes the importance of renal biopsy in the overall management of patients with DM and/or DN.(Internal Medicine 40:1077-1084, 2001)

Evaluation of renal biopsy samples of patients with diabetic nephropathy.

Glycation of proteins is regarded as one of the major causes of the development and progression of diabetic nephropathy. Based on the numerous reports on experimental models and on our own newly developed techniques, we planned to localize Amadori products and advanced glycation end-products (AGEs), as well as the mRNA expression of cytokines, enzymes and their inhibitors, which are responsible for the expansion of the mesangial areas of the glomeruli. Ten patients with diabetic nephropathy were examined. Patients with immunoglobulin (Ig) A nephropathy and normal portions of the surgically removed kidneys served as controls. Amadori products and AGEs in biopsy specimens were stained by specific monoclonal antibodies, and mRNA expression of the above substances was detected by in situ hybridization. There was a parallel progression in the degree of staining with anti-Amadori product antibody or anti-AGE antibody with the severity of tissue damage in patients with diabetic nephropathy. Patients with IgA nephropathy and normal renal tissues did not show any positive staining with these antibodies. The expression of transforming growth factor pi, stromelysin and tissue inhibitor of matrix proteinase 1 in the glomeruli was decreased in diabetic patients with advanced tissue damage, but they were progressively expressed in the advanced stage of IgA nephropathy. It is concluded that Amadori products and of AGEs were formed in parallel in diabetic kidneys. The decrease in the expression of the cytokine and enzymes might be due to altered protein formation associated with glycation.

Localization of glycated proteins in the glomeruli of patients with diabetic nephropathy

Background/Aim: Progressive expansion of mesangial matrix and glomerular basement membrane thickening represent alterations in the balance between synthesis and degradation of glomerular extracellular matrix (ECM) protein and are hallmarks of diabetic nephropathy. In order to elucidate the basis for this imbalance between the synthesis and the degradation of ECM in renal tissues from patients of type 1 diabetes mellitus (type 1D) with diabetic nephropathy (DN), we examined the expression of α1 chain of type IV collagen (IV-C), matrix metalloproteinase-2 and -3 (MMP-2, MMP-3), tissue inhibitor of metalloproteinase-1 (TIMP-1) and β-actin mRNA using a high-resolution in situ hybridization with digoxigenin-labeled oligonucleotide. Methods: Patients were divided into two groups based on both of degree of mesangial expansion using electron microscopic point counting morphometric methods and duration of type 1D: 7 ‘fast-track’ patients were selected for their very rapid development of DN structural changes and 8 ‘slow-track’ patients for their very slow development of DN structural changes. Seven normal human kidney (NHK) tissues were used as controls. Results: Positive cells for each mRNA were observed in glomerular resident cells, including glomerular mesangial, epithelial and endothelial cells and cells of Bowman’s capsule. The percentage of glomerular cells positive for IV-C, MMP-2 and MMP-3 mRNA was significantly greater in the ‘slow-track’ vs. ‘fast-track’ patients. No significant differences in percentage positive cells was seen for β-actin mRNA. Furthermore, to elucidate the total number of positive cells per glomerulus for each mRNA, we estimated total cell number of glomerulus using morphometric techniques on light microscopy tissues. The total cell number per glomerulus was significantly greater in ‘fast-track’ than that in ‘slow-track’ patients and NHK. The total number of positive cells per glomerulus for MMP-2 in NHK was significantly greater than that in ‘slow-track’ and ‘fast-track’ patients. Conclusion: Thus, IV-C, MMP-2, MMP-3 and TIMP-1 mRNA are expressed in resident glomerular cells in renal tissues from NHK and type 1D. Glomerular alterations in these in situ mRNA expressions sufficient to explain ECM accumulation and DN risk were not uncovered. These largely negative results could be due to methodologic quantitative imprecision or could indicate that post-translational differences account for ECM imbalance in DN. However, these studies make it clear that unraveling the nature of the ECM production/removal imbalance in DN will require careful consideration of alterations in glomerular cell number.

Renal in situ hybridization studies of extracellular matrix related molecules in type 1 diabetes mellitus.

Diabetic nephropathy is one of the major complications of diabetes mellitus and an important cause of increased morbidity and mortality in these patients. The increase in the number of patients with chronic renal failure due to diabetic nephropathy is a major problem in several countries. The pathogenesis of diabetic nephropathy therefore requires elucidation in order to develop effective treatment modalities. Several pathogenic mechanisms have been proposed, such as the presence of glomerular hyperfiltration and/or hyperperfusion [1], activation of the polyol pathway, myoinositol metabolism abnormalities [2, 3], high activity of protein kinase C [4, 5], increased nonenzymatic glycated proteins [6–9], hypercoagulability [10], involvement of cytokines and growth factors [11–14] and hereditary factors [15]. However, the precise mechanism remains to be clarified (table 1). The pathological hallmarks of diabetic nephropathy are increased thickness of the glomerular basement membrane (GBM) and mesangial expansion [16–20]. The latter is considered more significant than thickening of the GBM as expansion of the mesangium has been reported to ultimately lead to renal insufficiency [19]. These changes in the GBM and mesangium are characterized by expansion of all intrinsic components of extracellular glycoproteins, such as collagen types IV, V and VI, laminin, and fibronectin, as well as other intrinsic components of the normal renal extracellular matrix (ECM) that have not yet been identified [21–27]. Although the balance between ECM production and degradation is important, these relationships are not fully understood in diabetic nephropathy. Recent developments in cellular and molecular biology have allowed a better understanding of ECM production and degradation in this disease. This article reviews recent studies on the balance between ECM production and degradation and its role in the pathogenesis of diabetic nephropathy.

Metalloproteinases in the Pathogenesis of Diabetic Nephropathy

Summary: Immunohistochemical staining of glomeruli in patients with diabetic nephropathy (DN) in non-insulin dependent diabetes mellitus (NIDDM) using the monoclonal anti-advanced glycation end products (AGE) antibody is described. In order to detect the localization of AGE in human renal tissues, we performed immunohistochemical staining using the monoclonal anti-AGE antibody in the glomeruli of 11 patients with DN and 11 age-matched patients with diffuse mesangial proliferative glomerulonephritis without IgA deposition (DPGN) as controls.



Emergence of AGE in the mesangial area was more marked in the glomeruli of patients with severe mesangial expansion than in those with mild expansion. AGE in the extraglomerular arteriolar walls was also observed. In contrast, there was no positive staining using the same antibody in renal tissue obtained from DPGN.



These data support the concept that deposition and/or formation of AGE in the mesangial area might be associated with the progression of diabetic nephropathy.

Immunohistochemical staining of renal biopsy samples in patients with diabetic nephropathy in non‐insulin dependent diabetes mellitus using monoclonal antibody to advanced glycation end products

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Immunohistochemical staining of renal biopsy samples in patients with diabetic nephropathy in non‐insulin dependent diabetes mellitus using monoclonal antibody to advanced glycation end products