Potential role for Nrf2 activation in the therapeutic effect of MG132 on diabetic nephropathy in OVE26 diabetic mice

Abstract

Oxidative stress is a major cause of diabetic nephropathy. Upregulation of the key antioxidative transcription factor, nuclear factor-erythroid 2-related factor 2 (Nrf2), was found to prevent the development of diabetic nephropathy. The present study was designed to explore the therapeutic effect of Nrf2 induced by proteasomal inhibitor MG132 at a low dose (10 g/kg) on diabetic nephropathy. Transgenic type 1 diabetic (OVE26) mice displayed renal dysfunction with albuminuria by 3 mo of age, at which time MG132 treatment was started. After 3-mo treatment with MG132, renal function, morphology, and biochemical changes were examined with real-time PCR, Western blotting, and immunohistochemical examination. Compared with age-matched, nontreated diabetic mice, MG132-treated diabetic mice showed significant improvements in terms of renal structural and functional alterations. These therapeutic effects were associated with increased Nrf2 expression and transcriptional upregulation of Nrf2-regulated antioxidants. Mechanistic study using human renal tubular HK11 cells confirmed the role of Nrf2, as silencing the Nrf2 gene with its specific siRNA abolished MG132 prevention of high-glucose-induced profibrotic response. Furthermore, diabetes was found to significantly increase proteasomal activity in the kidney, an effect that was significantly attenuated by 3 mo of treatment with MG132. These results suggest that MG132 upregulates Nrf2 function via inhibition of diabetesincreased proteasomal activity, which can provide the basis for the therapeutic effect of MG132 on the kidney against diabetes-induced oxidative damage, inflammation, fibrosis, and eventual dysfunction. diabetic nephropathy; Nrf2; proteasome inhibitor; MG132; therapeutic effect

Combating oxidative stress in diabetic complications with Nrf2 activators: How much is too much?

“…39 Furthermore, silencing of Nrf2 abolishes MG132-mediated protection against high glucose-induced profibrotic responses in HK 11 cells. 65 These findings provide further proof that MG132 mediates its beneficial effects in diabetic complications, at least partly, through the activation of Nrf2 signalling.…”

“…The partial inhibition of proteasomal activity by MG132 at low doses may be therapeutically beneficial in diabetic complications; however, at higher doses it could exacerbate oxidative stress in the cell 67 and thereby induce apoptotic cell death. 65 …”

Leptin Level and Oxidative Stress Contribute to Obesity-Induced Low Testosterone in Murine Testicular Tissue

“…The transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf 2 ), is a central regulator of antioxidant and detoxification gene expression in response to electrophilic or oxidative stress [45]. Nrf 2 , a member of the Cap “n” Collar family of basic region leucine zipper transcription factors, plays an important role in preventing the development of oxidative stress through upregulation of Nrf 2 -related antioxidants [46, 47]. Moreover, Nrf 2 -knockout mice showed an oxidative disruption in spermatogenesis [48].…”

O papel do fator nuclear eritroide 2 relacionado ao fator 2 (Nrf2) no diabetes mellitus

“…Alguns estudos têm mostrado que o MG132, um potente, específico e reversível inibidor do proteassoma, aumenta os níveis do Nrf2 por diminuir sua degradação, dessa forma conferindo proteção aos rins 75 , coração 76 e aorta 77 contra os danos causados pelo DM. Contudo, deve ser observado que, apesar da inibição parcial da atividade do proteassoma em baixas doses ser terapeuticamente benéfica contra as complicações diabéticas, em doses elevadas o MG132 pode exacerbar o estresse oxidativo e, assim, induzir a morte celular por apoptose 75 . Assim sendo, o Nrf2 tem se tornado um alvo terapêutico promissor, pois a ativação do Nrf2 resulta em ativação de uma ampla gama de genes responsáveis pela proteção celular.…”