Nrf2 deficiency deteriorates diabetic kidney disease in Akita model mice
Yexin Liu,
Akira Uruno,
Ritsumi Saito,
Naomi Matsukawa,
Eiji Hishinuma,
Daisuke Saigusa,
Hong Liu,
Masayuki Yamamoto
Affiliations
Yexin Liu
Department 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
Akira Uruno
Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan; Corresponding author. Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, 9808575, Japan.
Ritsumi Saito
Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
Naomi Matsukawa
Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
Eiji Hishinuma
Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan; Advanced Research Center for Innovations in Next-Generation Medicine Tohoku University, Sendai, Japan
Daisuke Saigusa
Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan; Laboratory of Biomedical and Analytical Sciences, Faculty of Pharma-Science, Teikyo University, Tokyo, Japan
Hong Liu
Department of Nephrology, Blood Purification Center of the Second Xiangya Hospital, Central South University, Changsha, China
Masayuki Yamamoto
Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan; Corresponding author. Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, 9808575, Japan.
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.
