Hyperglycemia induces oxidative and nitrosative stress and increases renal functional impairment in Nrf2-deficient mice

Keigyou Yoh, Aki Hirayama, Kazusa Ishizaki, Akiko Yamada, Masayoshi Takeuchi, Sho Ichi Yamagishi, Naoki Morito, Takako Nakano, Masami Ojima, Homare Shimohata, Ken Itoh, Satoru Takahashi, Masayuki Yamamoto

Research output: Contribution to journalArticlepeer-review

186 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1159-1170
Number of pages12
JournalGenes to Cells
Issue number11
Publication statusPublished - 2008


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