Prevention of Streptozotocin-Induced Diabetic Nephropathy by MG132: Possible Roles of Nrf2 and IκB

Abstract EN

Our previous study showed that proteasomal inhibitor MG132 can prevent diabetic nephropathy (DN) along with upregulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2).

The present study was to investigate whether MG132 can prevent DN in wild-type and Nrf2-KO mice.

Type 1 diabetes was induced in wild-type and Nrf2-KO mice by multiple low doses of streptozotocin.

Two weeks after streptozotocin injection, both wild-type and Nrf2-KO mice were randomly divided into four groups: control, MG132, DM, and DM/MG132.

MG132 (10 μg/kg/day) or vehicle was administered intraperitoneally for 4 months.

Renal function, morphology, and biochemical changes were measured after 4-month treatment with MG132.

MG132 treatment suppressed proteasomal activity in the two genotypes.

In wild-type mice, MG132 attenuated diabetes-induced renal dysfunction, fibrosis, inflammation, and oxidative damage along with increased Nrf2 and IκB expression.

Deletion of Nrf2 gene resulted in a partial, but significant attenuation of MG132 renal protection in Nrf2-KO mice compared with wild-type mice.

MG132-increased IκB expression was not different between wild-type and Nrf2-KO mice.

This work indicates that MG132 inhibits diabetes-increased proteasomal activity, resulting in Nrf2 and IκB upregulation and renal protection, which could be used as a strategy to prevent diabetic nephropathy.