title: T Lymphocyte-Specific Activation of Nrf2 Protects from AKI.
abstract: T lymphocytes are established mediators of ischemia reperfusion (IR)-induced AKI, but traditional immune principles do not explain their mechanism of early action in the absence of alloantigen. Nrf2 is a transcription factor that is crucial for cytoprotective gene expression and is generally thought to have a key role in dampening IR-induced AKI through protective effects on epithelial cells. We proposed an alternative hypothesis that augmentation of Nrf2 in T cells is essential to mitigate oxidative stress during IR-induced AKI. We therefore generated mice with genetically amplified levels of Nrf2 specifically in T cells and examined the effect on antioxidant gene expression, T cell activation, cytokine production, and IR-induced AKI. T cell-specific augmentation of Nrf2 significantly increased baseline antioxidant gene expression. These mice had a high frequency of intrarenal CD25(+)Foxp3(+) regulatory T cells and decreased frequencies of CD11b(+)CD11c(+) and F4/80(+) cells. Intracellular levels of TNF-α, IFN-γ, and IL-17 were significantly lower in CD4(+) T cells with high Nrf2 expression. Mice with increased T cell expression of Nrf2 were significantly protected from functional and histologic consequences of AKI. Furthermore, adoptive transfer of high-Nrf2 T cells protected wild-type mice from IR injury and significantly improved their survival. These data demonstrate that T cell-specific activation of Nrf2 protects from IR-induced AKI, revealing a novel mechanism of tissue protection during acute injury responses.
authors: Division of Nephrology, Department of Medicine and.
authors: Sanjeev
authors: S
authors: Noel
authors: Division of Immunopathology, Department of Pathology, Johns Hopkins University, Baltimore, Maryland; and.
authors: Maria N
authors: MN
authors: Martina
authors: Division of Nephrology, Department of Medicine and.
authors: Samatha
authors: S
authors: Bandapalle
authors: Division of Immunopathology, Department of Pathology, Johns Hopkins University, Baltimore, Maryland; and.
authors: Lorraine C
authors: LC
authors: Racusen
authors: Department of Pediatrics, College of Medicine, University of Illinois, Chicago, Illinois.
authors: Haranatha R
authors: HR
authors: Potteti
authors: Division of Immunopathology, Department of Pathology, Johns Hopkins University, Baltimore, Maryland; and.
authors: Abdel R A
authors: AR
authors: Hamad
authors: Department of Pediatrics, College of Medicine, University of Illinois, Chicago, Illinois.
authors: Sekhar P
authors: SP
authors: Reddy
authors: Division of Nephrology, Department of Medicine and hrabb1@jhmi.edu.
authors: Hamid
authors: H
authors: Rabb
mesh_terms: D058186:Acute Kidney Injury / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D019264:Adoptive Transfer; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics; D005784:Gene Amplification; D015870:Gene Expression; D051547:Heme Oxygenase-1 / Q000235:genetics; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D008213:Lymphocyte Activation / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism; D015427:Reperfusion Injury / Q000150:complications / Q000276:immunology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000975:Antioxidants; D003598:Cytoskeletal Proteins; D020381:Interleukin-17; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse
keywords: AKI; Nrf2-Keap1; T cell; inflammation; oxidative stress