Hyperglycemia induces oxidative and nitrosative stress and increases renal functional impairment in Nrf2-deficient mice.
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.
Yoh
Keigyou
K
Pathophysiology of Renal Diseases, Doctoral Program in Clinical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba 305-8575, Japan.
Hirayama
Aki
A
Ishizaki
Kazusa
K
Yamada
Akiko
A
Takeuchi
Masayoshi
M
Yamagishi
Sho-ichi
S
Morito
Naoki
N
Nakano
Takako
T
Ojima
Masami
M
Shimohata
Homare
H
Itoh
Ken
K
Takahashi
Satoru
S
Yamamoto
Masayuki
M
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
C481144:8-nitroguanosine; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D009566:Nitrates; D009573:Nitrites; D009574:Nitro Compounds; D006151:Guanosine