Aim: To determine the effects of a novel GPx-mimetic, m-hydroxyebselen (ME), in attenuating diabetic nephropathy in ApoE-/-/GPx1-/- mice.

Background: The expression and activity of the antioxidant, GPx1, is reduced in diabetes. More importantly, a defective GPx1 defence mechanism is associated with more severe glomerulosclerosis and mesangial expansion in both diabetic rats and humans. We therefore propose that by replenishing the activity of GPx1 with a synthetic mimetic, kidney disease associated with diabetes will be attenuated in ApoE-/-/GPx1-/- mice.

Methods: In in vitro studies, NRK52E cells were used to examine the anti-oxidative effects of ME. In in vivo studies, ApoE-/-/GPx1-/- mice were injected with STZ to induce diabetes. After two weeks, mice were gavaged with either ME at 10mg/kg twice daily, or vehicle (5% CMC) for 14 weeks. At the end of the study, urine was collected for albumin to creatinine ratio (ACR) measurements and kidney tissues were collected for histological analyses.

Results: ME significantly reduced the production of ROS in NRK52E cells following stimulation with H2O2. Histological analyses showed that diabetic mice displayed significant increase in tubulointerstitial fibrosis and glomerulosclerosis, both of which were attenuated by the treatment with ME. The ACR was increased in diabetic mice and treatment with ME showed a trend of reduction in diabetic mice versus vehicle-treated group.

Conclusions: By replenishing the activity of GPx, oxidative stress and renal fibrosis were attenuated, potentially leading to an improvement in renal function in a mouse model of diabetic nephropathy.