title: 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.affiliation: Second Hospital of Jilin University, Changchun, China.
authors.forename: Wenpeng
authors.initials: W
authors.lastname: Cui
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.forename: Yang
authors.initials: Y
authors.lastname: Bai
authors.forename: Xiao
authors.initials: X
authors.lastname: Miao
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chen
authors.forename: Weixia
authors.initials: W
authors.lastname: Sun
authors.forename: Yi
authors.initials: Y
authors.lastname: Tan
authors.forename: Ping
authors.initials: P
authors.lastname: Luo
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.forename: Shirong
authors.initials: S
authors.lastname: Zheng
authors.forename: Paul N
authors.initials: PN
authors.lastname: Epstein
authors.forename: Lining
authors.initials: L
authors.lastname: Miao
authors.forename: Lu
authors.initials: L
authors.lastname: Cai
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy / Q000235:genetics; D003928:Diabetic Nephropathies / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D007976:Leupeptins / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D013311:Streptozocin; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology
chemical_list: D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D034741:RNA, Small Interfering; D013311:Streptozocin; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde