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

doi:10.1016/j.redox.2022.102525

Nrf2 deficiency deteriorates diabetic kidney disease in Akita model mice

Redox Biol. 2022 Dec:58:102525. doi: 10.1016/j.redox.2022.102525. Epub 2022 Oct 28.

Authors

Yexin Liu¹, Akira Uruno², Ritsumi Saito³, Naomi Matsukawa⁴, Eiji Hishinuma⁵, Daisuke Saigusa⁶, Hong Liu⁷, Masayuki Yamamoto⁸

Affiliations

¹ 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.
² Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan. Electronic address: uruno@med.tohoku.ac.jp.
³ Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
⁴ Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
⁵ 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.
⁶ 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.
⁷ Department of Nephrology, Blood Purification Center of the Second Xiangya Hospital, Central South University, Changsha, China.
⁸ Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan. Electronic address: masiyamamoto@med.tohoku.ac.jp.

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 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.

Keywords: Diabetic kidney disease; Glutathione; Inflammation; MALDI-MSI; Nrf2; Oxidative stress.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Diabetes Mellitus, Experimental* / complications
Diabetes Mellitus, Experimental* / physiopathology
Diabetic Nephropathies* / genetics
Diabetic Nephropathies* / physiopathology
Glutathione / metabolism
Inflammation / metabolism
Kelch-Like ECH-Associated Protein 1 / genetics
Kelch-Like ECH-Associated Protein 1 / metabolism
Kidney / metabolism
Mice
Mice, Inbred C57BL
NF-E2-Related Factor 2* / genetics
Oxidative Stress

Substances

Glutathione
Kelch-Like ECH-Associated Protein 1
NF-E2-Related Factor 2
Nfe2l2 protein, mouse