ACCUMULATION OF N-EPSILON-(CARBOXYMETHYL)LYSINE AND CHANGES IN GLOMERULAR EXTRACELLULAR-MATRIX COMPONENTS IN OTSUKA LONG-EVANS TOKUSHIMA FATTY RAT - A MODEL OF SPONTANEOUS NIDDM

Increases in extracellular matrix (ECM) and changes in its components have been documented in the glomeruli of diabetic nephropathy. Advance d glycation end products formed by glycoxidation have been shown to in duce the synthesis of ECM components and transforming growth factor be ta (TGF-beta), suggesting that advanced glycation end products may be involved in the etiology of imbalance of ECM components in diabetic gl omerulosclerosis. The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an inbred strain that spontaneously develops non-insulin-dependent di abetes mellitus which progresses to diabetic glomerulosclerosis. N-eps ilon-(carboxymethyl)lysine (CML) is known to be formed by glycoxidatio n. To clarify the involvement of glycoxidation in diabetic nephropathy , we examined the localization of CML, ECM components, and TGF-beta(1) in the glomeruli of OLETF rats. The amounts of alpha(3)(IV) collagen, type VI collagen, and fibronectin were significantly increased in the glomeruli of OLETF rats, whereas the heparan sulfate proteoglycan lev els were decreased. After 6 months of age, CML levels were significant ly increased in the mesangial area of the glomeruli in these animals. The overexpression of TCF-beta(1) preceded the increase in glomerular ECM components. The present study demonstrated that the accumulation o f CML precedes the changes of glomerular ECM components in the glomeru li during the course of diabetic nephropathy, suggesting that glycoxid ation may be one of the major causes of diabetic glomerulosclerosis.