Hyperhomocysteinemia is known to be associated with many of the occlusive vascular diseases including ischemic heart disease. Elevated plasma total homocysteine (t-Hcy) is also remarkably common among patients with moderate to severe renal failure. The purpose of this study was to investigate the role of homocysteine (Hcy) in the pathogenesis of diabetic nephropathy in the rat. Additionally, any effect of aminoguanidine (AG), an inhibitor of advanced glycation end product (AGE) formation, on the onset of nephropathic symptoms and on the concentrations of Hey was searched for. Diabetes was induced in male Wistar albino rats (6 months old) by a single injection of 50 mg kg(-1) streptozotocin (STZ) into the penile vein. Animals with blood glucose levels higher than 350 mg dl(-1) 72 It after STZ injection were included in the study. Age-matched rats receiving a single dose of citrate buffer served as controls. One half of the control and diabetic groups received AG via drinking water (1 g l(-1)). The experimental period lasted for ten weeks. Animals were killed by cardiac venipuncture after 24 hour urine samples were collected. Serum t-Hcy was quantified using HPLC, and urinary GAGS using the spectrophotometric 1,9-dimethyl methylene blue dye method. Serum glucose. protein, creatinine and total sulfydryl (t-SH) measurements, and urinary protein determinations were carried out spectrophotometrically. In diabetic rats, serum t-Hcy levels were significantly decreased (P < 0.001), and were negatively correlated with the urinary protein concentration (r = -0.67, P < 0.05). Urinary GAG levels were also increased in diabetic rats (P < 0.001). AG neither affected the t-Hcy levels, nor ameliorated the nephropathic symptoms. These results indicate that diabetic nephropathy is not linked to homocysteinemia in the rat. (C) 2002 Elsevier Science Ltd.