Advanced glycation end products (AGEs) include a variety of
protein adducts whose accumulation alters the structure and function of tissue
proteins and stimulates cellular responses. They have been implicated in tissue damage associated with
diabetic complications. To assess the possible link between AGE accumulation and the development of
diabetic nephropathy (DN), we have examined the immunohistochemical localization of various AGE structures postulated to date, i.e.,
pentosidine, Nepsilon-(
carboxymethyl)lysine (CML), and
pyrraline, in diabetic and control kidneys. CML and
pentosidine accumulate in the expanded mesangial matrix and thickened glomerular capillary walls of early DN and in nodular lesions and arterial walls of advanced DN, but were absent in control kidneys. By contrast,
pyrraline was not found within diabetic glomeruli but was detected in the interstitial connective tissue of both normal and diabetic kidneys. Although the distribution of
pyrraline was topographically identical to
type III collagen, distribution of
pentosidine and CML was not specific for
collagen type, suggesting that difference in matrix
protein composition per se could not explain heterogeneous AGE localization. Since oxidation is linked closely to the formation of
pentosidine and CML, we also immunostained
malondialdehyde (MDA), a lipid peroxidation product whose formation is accelerated by oxidative stress, assuming that local oxidative stress may serve as a mechanism of
pentosidine and CML accumulation. Consistent with our assumption, diabetic nodular lesions were stained positive for MDA. These findings show that AGE localization in DN varies according to AGE structure, and suggest that the colocalization of markers of glycoxidation (
pentosidine and CML) with a marker of lipid peroxidation reflects a local oxidative stress in association with the pathogenesis of diabetic glomerular lesions. Thus, glycoxidation markers may serve as useful
biomarkers of oxidative damage in DN.