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 μg/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 diabetes-increased 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.

• Authors: Wenpeng Cui, Bing Li, Yang Bai, Xiao Miao, Qiang Chen, Weixia Sun, Yi Tan, Ping Luo, Chi Zhang, Shirong Zheng, Paul N Epstein, Lining Miao, Lu Cai
• Journal: American journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 304 Issue 1 Pg. E87-99 (Jan 01 2013) ISSN: 1522-1555 [Electronic] United States
• PMID: 23132297 (Publication Type: Comparative Study, Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cysteine Proteinase Inhibitors
• Leupeptins
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• RNA, Small Interfering
• Streptozocin
• benzyloxycarbonylleucyl-leucyl-leucine aldehyde

Topics

• Animals
• Cells, Cultured
• Cysteine Proteinase Inhibitors (therapeutic use)
• Diabetes Mellitus, Experimental (chemically induced, complications, drug therapy, genetics)
• Diabetic Nephropathies (chemically induced, drug therapy, genetics)
• Female
• Gene Expression Regulation (drug effects)
• Kidney (drug effects, metabolism, physiology)
• Leupeptins (therapeutic use)
• Mice
• Mice, Transgenic
• NF-E2-Related Factor 2 (antagonists & inhibitors, genetics, metabolism, physiology)
• RNA, Small Interfering (pharmacology)
• Streptozocin
• Transcriptional Activation (drug effects, physiology)