| BackgroundMany reports have demonstrated that increased oxidative stress in diabetes plays an important role in the progression of diabetic complications, including nephropathy . Oxidative stress is determined by the relationship between reactive oxygen species (ROS) and the antioxidant defense system including antioxidant enzymes. ROS has been implicated in the pathogenesis of diabetes mellitus. Increased ROS leads to lipid peroxidation which amplifies oxidative injury and causes damage to biomacromolecules such as protein and nucleic acid. Many mechanisms are involved in the production of ROS including glucose autoxidation, non-enzyme protein glycation, generation of advanced glycation end products (AGE), activation of protein kinase C (PKC) and NADPH oxidase. It has been demonstrated that glomeruli are especially sensitive to oxidative injury that contributes to the progression of diabetic nephropathy.HMG-CoA reductase inhibitors (statins), including simvastatin, have been shown to be effective lipid-lowering agents. Recently, many studies have demonstrated that statins have pleiotropic effects independent of their cholesterol-lowering effects. A report by Jones et al. suggested that statins have antioxidative effects that benefit cardiac myocytes. Rikitake et al. demonstrated the antioxidative properties of fluvastatin which intercept atherosclerosis in cholesterol-fed rabbits. Statins also have protective effects on glomeruli, but the precise mechanisms remain unclear.The present study was designed to investigate the effects of simvastatin on oxidative stress as well as on the antioxidative defense system and how these affect early stage diabetic nephropathy by analysis of proteinuria and glomerular morphometry in streptozotocin (STZ)-induced diabetic rats. Materials and MethodsAt week 6, 9 rats from DM+S group, 9 rats from DM group and 10 rats from CN group as well as the other rats at week 12 were sacrificed under pentobarbital anesthesia (5 mg/100 g). 24-Hour urine was collected for measurement of 24-hour urinary albumin excretion (UAE). 5 ml of blood was collected from the femoral artery with 3 ml centrifuged to obtain serum for measurement of serum glucose (GLU), creatinine (SCr), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides (TG). The other 2 ml in an anticoagulant tube containing sodium EDTA was divided into plasma and erythrocytes by centrifugation at 2,000 gfor 10 min at 4°C. Erythrocyte samples were washed 3 times in cold isotonic saline (0.9%) and then hemolyzed with 4-fold the volume of distilled water. Plasma and hemolyzed erythrocytes were used for measurement of lipid peroxidation production as malondialdehyde in plasma (MDAp) and erythrocytes (MDAe) and activity of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST). Kidneys were excised, weighed and used for tissue structure morphometry. Renal tissues fixed in 10% formalin and embedded in paraffin were cut into 3-μm sections and stained with periodic acid-Schiff (PAS). Ten glomeruli of each animal were examined for glomerular volume (GV) and mesangial area(M/T). ResultsAt weeks 6 and 12, BW and KW of both the DM group and the DM+S group were decreased (p < 0.05) while KW/BW was significantly increased (p < 0.05) compared with the CN group. No significant differences of these parameters were found between the two diabetes groups. UAE was significantly increased in both of the diabetes groups compared with the CN group while it was more enhanced in the DM group (p < 0.05). In both of the diabetes groups, BW at week 12 was significantly lower (p < 0.05) than that at week 6, while KW and KW/BW at week 12 were higher (p < 0.05) than at week 6. In the CN group, BW and KW at week 12 were higher (p < 0.05) than those at week 6, while significant differences in KW/BW were notfound between weeks 6 and 12. Mutual effects were not observed in the parameters above between groups and experimental weeks.The glucose level in both of the diabetes groups was sign... |
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