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Hyperglycemia induces oxidative and nitrosative stress and increases renal functional impairment in Nrf2-deficient
Keigyou Yoh1, Aki Hirayama, Kazusa Ishizaki
1Pathophysiology of Renal Diseases, Doctoral Program in Clinical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba 305-8575, Japan.
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.
Insights
Nuclear factor erythroid 2-related factor 2 (Nrf2) protects against diabetic kidney injury. Nrf2 knockout mice showed accelerated renal damage and increased oxidative stress, highlighting Nrf2
Area of Science:
- Nephrology
- Metabolic diseases
- Molecular biology
Background:
- Diabetes mellitus is characterized by hyperglycemia, leading to oxidative stress and kidney complications.
- The role of the transcription factor Nrf2, a regulator of antioxidant genes, in diabetic nephropathy is not fully understood.
Purpose of the Study:
- To investigate the protective role of Nrf2 in the development of diabetic kidney disease.
- To elucidate the impact of Nrf2 deficiency on hyperglycemia-induced renal dysfunction and oxidative stress.
Main Methods:
- Streptozotocin (STZ)-induced diabetes model in Nrf2 knockout (Nrf2 KO) and wild-type (WT) mice.
- Assessment of renal function, including hyperfiltration and glomerular filtration rate.
- Measurement of urinary nitric oxide metabolites and detection of 8-nitroguanosine in renal lesions.
- In vivo electron paramagnetic resonance (EPR) spectroscopy to evaluate oxidative stress.
Main Results:
- STZ-treated Nrf2 KO mice did not exhibit renal hyperfiltration but showed progressive renal function deterioration.
- Increased urinary nitric oxide metabolites and 8-nitroguanosine in glomerular lesions were observed in STZ Nrf2 KO mice.
- EPR analysis indicated accelerated oxygen radical formation in STZ Nrf2 KO mice, evidenced by faster spin probe signal decay.
Conclusions:
- Hyperglycemia exacerbates oxidative and nitrosative stress in Nrf2-deficient mice, accelerating renal injury.
- Nrf2 acts as a crucial defense factor, mitigating specific complications associated with diabetic nephropathy.
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