Renoprotective and lipid-lowering effects of LR compounds, novel advanced glycation end product inhibitors, in streptozotocin-induced diabetic rats.

The accelerated formation of advanced glycation/lipoxidation end products (AGEs/ALEs) has been implicated in the pathogenesis of various diabetic complications. Several natural and synthetic compounds have been proposed and advanced as inhibitors of AGE/ALE formation. We examined the effects of two new AGE/ALE inhibitors, LR-9 and LR-74, on the prevention of early renal disease and dyslipidemia in streptozotocin (STZ)-induced diabetic rats. Diabetic rats were treated with either LR-9 or LR-74 for 32 weeks. Progression of renal disease was evaluated by measurements of urinary albumin and plasma creatinine concentrations. AGE-induced chemical modification of the tail tendon collagen and levels of Nepsilon-(carboxymethyl)- and (carboxyethyl)- lysines (CML and CEL) in skin collagen were measured. AGE/ALE levels in kidneys were determined by immunohistochemistry. Plasma lipids and their lipid hydroperoxide concentrations were also determined. Treatment of either LR-9 or LR-74 significantly inhibited the increase in albuminuria, plasma creatinine, hyperlipidemia, and plasma lipid peroxidation in diabetic rats without any effects on hyperglycemia. Both compounds also reduced CML-AGE accumulation in kidney glomeruli and tubules, AGE-linked fluorescence and cross-linking of tail collagen, and levels of CML and CEL in skin collagen. These results suggest that both LR compounds can inhibit the progression of renal disease and also prevent dyslipidemia in experimental diabetes. These compounds may have an additional beneficial effect as an antioxidant against lipid peroxidation, and thus may provide alternative therapeutic options for the treatment of various diabetic macrovascular complications.