title: Hyperglycemia induces oxidative and nitrosative stress and increases renal functional impairment in Nrf2-deficient mice.
abstract: The transcription factor Nrf2 regulates the expression of antioxidant genes. Hyperglycemia-induced oxidative stress is involved in the pathogenesis of diabetes and its complications. However, little is known about the protective role of Nrf2 in diabetes. To gain insight into the protective role of Nrf2 in diabetes we treated Nrf2 knockout (Nrf2 KO) mice with streptozotocin (STZ). The STZ Nrf2 KO mice did not develop renal hyperfiltration, which was observed in the STZ-treated wild-type (STZ WT) mice, but renal function gradually deteriorated over the 10-week observation period. Urinary excretion of nitric oxide metabolites and the occurrence of 8-nitroguanosine, which was detected in glomerular lesions, were increased in STZ Nrf2 KO mice during the early stages after treatment. In vivo electron paramagnetic resonance analysis revealed an accelerated rate of decay of the 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl spin probe signal in STZ Nrf2 KO mice. The addition of superoxide dismutase prolonged the half-life of the signal, which suggested that increased oxygen radical formation occurred in the STZ Nrf2 KO mice. These results suggested that hyperglycemia increased oxidative and nitrosative stress and accelerated renal injury in the Nrf2 KO mice and that Nrf2 serves as a defense factor against some diabetic complications.
authors.affiliation: Pathophysiology of Renal Diseases, Doctoral Program in Clinical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba 305-8575, Japan.
authors.forename: Keigyou
authors.initials: K
authors.lastname: Yoh
authors.forename: Aki
authors.initials: A
authors.lastname: Hirayama
authors.forename: Kazusa
authors.initials: K
authors.lastname: Ishizaki
authors.forename: Akiko
authors.initials: A
authors.lastname: Yamada
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Sho-ichi
authors.initials: S
authors.lastname: Yamagishi
authors.forename: Naoki
authors.initials: N
authors.lastname: Morito
authors.forename: Takako
authors.initials: T
authors.lastname: Nakano
authors.forename: Masami
authors.initials: M
authors.lastname: Ojima
authors.forename: Homare
authors.initials: H
authors.lastname: Shimohata
authors.forename: Ken
authors.initials: K
authors.lastname: Itoh
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D004578:Electron Spin Resonance Spectroscopy; D005260:Female; D006151:Guanosine / Q000031:analogs & derivatives / Q000378:metabolism; D006943:Hyperglycemia / Q000150:complications / Q000378:metabolism*; D007674:Kidney Diseases / Q000209:etiology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D009574:Nitro Compounds / Q000378:metabolism; D015538:Nitrosation; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D044967:Serum / Q000378:metabolism
chemical_list: C481144:8-nitroguanosine; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D009566:Nitrates; D009573:Nitrites; D009574:Nitro Compounds; D006151:Guanosine