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

Lining Miao,Lili Kong,Manyu Luo,Wenpeng Cui,Yi Tan,Yangwei Wang

doi:10.1155/2017/3671751

Abstract

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.

Highlights

Diabetic nephropathy (DN) is the leading cause of endstage renal failure worldwide
The results revealed that streptozotocin-injected nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-KO mice had a higher level of Urinary Albumin to Creatinine Ratio (UACR) than wild-type mice, indicating the essential role of Nrf2 in protecting against streptozotocininduced renal injury
MG132 decreased UACR and kidney weight/tibia length by 55.1% and 29.0% in wild-type diabetic mice and by 27.9% and 20.6% in Nrf2-KO mice, respectively; these effects were significantly lower in Nrf2-KO mice (Figure 1(e))

Summary

Introduction

Diabetic nephropathy (DN) is the leading cause of endstage renal failure worldwide. DN is linked to a high risk of cardiovascular disease. Albuminuria and glomerular filtration rate were suggested to have relevant prognostic effects on cardiovascular morbidity and mortality, and the effect of albuminuria is especially pronounced when glomerular filtration rate is normal or near normal [2] Both end-stage renal failure and cardiovascular disease brought us a heavy social burden. It is of vital importance and urgency to find more effective therapeutic strategies in countering the diabetesassociated renal injury. MG132 inhibited nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and IkB proteasomal degradation, resulting in antioxidative stress and antiinflammation function, respectively. Our previous study showed that nontoxic concentrations of MG132 could inhibit Nrf proteasomal degradation, leading to the renal protection of MG132 against diabetes-induced. We want to know whether renoprotection of MG132 was totally Nrf2dependent

Materials and Methods

Results

Discussion