Background and Aim: Previous studies have shown that preventive treatment with ebselen, a mimic of the antioxidant glutathione peroxidase, in experimental models of type 1 diabetic nephropathy resulted in an attenuation of structural and functional damage in the kidney. However, evidence for the effectiveness of ebselen in late-intervention studies is lacking. Thus, we aimed to investigate the effects of ebselen in attenuating established renal damage in type 1 diabetic nephropathy using the Akita mouse model.
Methods: Baseline blood glucose (BG) and albumin excretion rate (AER) were measured in wildtype (WT) and heterozygous (HTZ) Akita mice at 9-week of age. At 10-week of age, WT and HTZ Akita mice were randomised to receive either vehicle or ebselen by oral gavage at 10mg/kg twice daily. Kidney and urine were collected after 16 weeks of treatment with ebselen for histological and functional analyses.
Results: At 9-week of age, HTZ Akita mice displayed well-established renal dysfunction with significant increase in AER when compared to WT controls (38 vs 221µg/24hr, P<0.0001). After treatment with ebselen for 16 weeks, oxidative stress, as measured by nitrotyorosine immunostaining (7.5% vs 5.6%, P<0.05) and urinary 8-OHdG levels (85 vs 72 ng/µmol creatinine, P<0.01), was significantly reduced by ebselen in the HTZ Akita mice. Furthermore, gene expression of the major ROS-producing NADPH enzyme, Nox4, was also reduced by ebselen (1.9 vs 0.9 fold change compared to WT control, P<0.01). However, AER and glomerulosclerosis were not affected by ebselen treatment.
Conclusion: Chronic treatment with ebselen significantly reduced oxidative stress in the HTZ Akita mice. However, it failed to attenuate functional or structural kidney damage in this late-intervention study using the Akita mouse model.