title: Prevention of Streptozotocin-Induced Diabetic Nephropathy by MG132: Possible Roles of Nrf2 and IκB.
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 (10μg/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 ofNrf2gene 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.
authors.affiliation: Department of Nephrology, The Second Hospital of Jilin University, Changchun, Jilin, China; Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, China; Department of Pediatrics, University of Louisville, Louisville, KY, USA.
authors.forename: Lili
authors.identifier: 0000-0002-0674-1155
authors.initials: L
authors.lastname: Kong
authors.affiliation: Department of Nephrology, The Second Hospital of Jilin University, Changchun, Jilin, China.
authors.forename: Yangwei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Nephrology, The Second Hospital of Jilin University, Changchun, Jilin, China.
authors.forename: Manyu
authors.identifier: 0000-0002-3081-2793
authors.initials: M
authors.lastname: Luo
authors.affiliation: Department of Pediatrics, University of Louisville, Louisville, KY, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Department of Nephrology, The Second Hospital of Jilin University, Changchun, Jilin, China.
authors.forename: Wenpeng
authors.identifier: 0000-0001-6637-7255
authors.initials: W
authors.lastname: Cui
authors.affiliation: Department of Nephrology, The Second Hospital of Jilin University, Changchun, Jilin, China.
authors.forename: Lining
authors.initials: L
authors.lastname: Miao
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects; D007976:Leupeptins / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D011897:Random Allocation; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D007976:Leupeptins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde