Transcription factor Nrf2 is protective during ischemic and nephrotoxic acute kidney injury in mice.
Oxidative stress is involved in acute kidney injury due to ischemia-reperfusion and chemotherapy-induced nephrotoxicity. To investigate their basic mechanisms we studied the role of nuclear factor-erythroid 2-p45-related factor 2 (Nrf2), a redox-sensitive transcription factor that regulates expression of several antioxidant and cytoprotective genes. We compared the responses of Nrf2-knockout mice and their wild-type littermates in established mouse models of ischemia-reperfusion injury and cisplatin-induced nephrotoxicity. Several Nrf2-regulated genes encoding antioxidant enzymes/proteins were significantly upregulated in the kidneys of wild type but not Nrf2-knockout mice following renal ischemia. Renal function, histology, vascular permeability, and survival were each significantly worse in the Nrf2 knockout mice. Further, proinflammatory cytokine and chemokine expression tended to increase after ischemia in the knockout compared to the wild-type mice. Treatment of the knockout mice with the antioxidants N-acetyl-cysteine or glutathione improved renal function. The knockout mice were more susceptible to cisplatin-induced nephrotoxicity, and this was blunted by N-acetyl-cysteine pretreatment. Our study demonstrates that Nrf2-deficiency enhances susceptibility to both ischemic and nephrotoxic acute kidney injury, and identifies this transcription factor as a potential therapeutic target in these injuries.
Liu
Manchang
M
Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205, USA. mliu13@jhmi.edu
Grigoryev
Dmitry N
DN
Crow
Michael T
MT
Haas
Mark
M
Yamamoto
Masayuki
M
Reddy
Sekhar P
SP
Rabb
Hamid
H
D000111:Acetylcysteine / Q000494:pharmacology; D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D002199:Capillary Permeability; D002945:Cisplatin / Q000633:toxicity; D005978:Glutathione / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000473:pathology; D007677:Kidney Function Tests; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D015427:Reperfusion Injury / Q000378:metabolism*; D015854:Up-Regulation
D000970:Antineoplastic Agents; D018836:Inflammation Mediators; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D005978:Glutathione; D002945:Cisplatin; D000111:Acetylcysteine