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Nrf2 deficiency deteriorates diabetic kidney disease in Akita model mice
Yexin Liu1, Akira Uruno2, Ritsumi Saito2
1Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Nephrology, Blood Purification Center of the Second Xiangya Hospital, Central South University, Changsha, China.
Abstract:
Oxidative stress is an essential component in the progression of diabetic kidney disease (DKD), and the transcription factor NF-E2-related factor-2 (Nrf2) plays critical roles in protecting the body against oxidative stress. To clarify the roles of Nrf2 in protecting against DKD, in this study we prepared compound mutant mice with diabetes and loss of antioxidative defense. Specifically, we prepared compound Ins2Akita/+ (Akita) and Nrf2 knockout (Akita::Nrf2-/-) or Akita and Nrf2 induction (Akita::Keap1FA/FA) mutant mice. Eighteen-week-old Akita::Nrf2-/- mice showed more severe diabetic symptoms than Akita mice. In the Akita::Nrf2-/- mouse kidneys, the glomeruli showed distended capillary loops, suggesting enhanced mesangiolysis. Distal tubules showed dilation and an increase in 8-hydroxydeoxyguanosine-positive staining. In the Akita::Nrf2-/- mouse kidneys, the expression of glutathione (GSH) synthesis-related genes was decreased, and the actual GSH level was decreased in matrix-assisted laser desorption/ionization mass spectrometry imaging analysis. Akita::Nrf2-/- mice exhibited severe inflammation and enhancement of infiltrated macrophages in the kidney. To further examine the progression of DKD, we compared forty-week-old Akita mouse kidney compounds with Nrf2-knockout or Nrf2 mildly induced (Akita::Keap1FA/FA) mice. Nrf2-knockout Akita (Akita::Nrf2-/-) mice displayed severe medullary cast formation, but the formation was ameliorated in Akita::Keap1FA/FA mice. Moreover, in Akita::Keap1FA/FA mice, tubule injury and inflammation-related gene expression were significantly suppressed, which was evident in Akita::Nrf2-/- mouse kidneys. These results demonstrate that Nrf2 contributes to the protection of the kidneys against DKD by suppressing oxidative stress and inflammation.
Insights
The transcription factor Nrf2 protects kidneys from diabetic kidney disease (DKD) by reducing oxidative stress and inflammation. Loss of Nrf2 worsens DKD symptoms, while its induction ameliorates kidney damage.
Area of Science:
- Nephrology
- Molecular Biology
- Genetics
Background:
- Diabetic kidney disease (DKD) is a major complication of diabetes, characterized by oxidative stress.
- The transcription factor NF-E2-related factor-2 (Nrf2) is a key regulator of cellular antioxidant defense.
- Understanding Nrf2's role in DKD is crucial for developing therapeutic strategies.
Purpose of the Study:
- To investigate the protective role of Nrf2 against the progression of diabetic kidney disease (DKD).
- To elucidate the mechanisms by which Nrf2 modulates oxidative stress and inflammation in DKD.
Main Methods:
- Generation of compound mutant mice: Ins2Akita/+ (Akita) crossed with Nrf2 knockout (Nrf2-/-) or Keap1FA/FA mice.
- Assessment of diabetic symptoms, kidney pathology (glomeruli, tubules), oxidative stress markers (8-hydroxydeoxyguanosine), glutathione levels, and inflammation.
- Comparative analysis of Akita::Nrf2-/- and Akita::Keap1FA/FA mice at different ages.
Main Results:
- Nrf2 knockout (Akita::Nrf2-/-) mice exhibited exacerbated DKD symptoms, including mesangiolysis, tubular dilation, increased oxidative stress, and reduced glutathione levels.
- Akita::Nrf2-/- mice showed severe kidney inflammation and macrophage infiltration.
- Mild Nrf2 induction (Akita::Keap1FA/FA) ameliorated medullary cast formation, suppressed tubule injury, and reduced inflammation compared to Nrf2 knockout mice.
Conclusions:
- Nrf2 plays a significant protective role in mitigating kidney damage during diabetic kidney disease.
- Nrf2 exerts its protective effects by suppressing oxidative stress and inflammation in the renal tissue.
- Targeting Nrf2 activation may represent a promising therapeutic approach for DKD treatment.
