Nrf2 deficiency deteriorates diabetic kidney disease in Akita model mice

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 Ins2(Akita/+) (Akita) and Nrf2 knockout (Akita::Nrf2(−/−)) or Akita and Nrf2 induction (Akita::Keap1(FA/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::Keap1(FA/FA)) mice. Nrf2-knockout Akita (Akita::Nrf2(−/−)) mice displayed severe medullary cast formation, but the formation was ameliorated in Akita::Keap1(FA/FA) mice. Moreover, in Akita::Keap1(FA/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.