T Lymphocyte-Specific Activation of Nrf2 Protects from AKI

• Published in: Journal of the American Society of Nephrology 2015-12, Vol.26 (12), p.2989-3000
• Main Authors: Noel, Sanjeev, Martina, Maria N, Bandapalle, Samatha, Racusen, Lorraine C, Potteti, Haranatha R, Hamad, Abdel R A, Reddy, Sekhar P, Rabb, Hamid
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury - immunology; Acute Kidney Injury - metabolism; Acute Kidney Injury - pathology; Adaptor Proteins, Signal Transducing - genetics; Adoptive Transfer; Animals; Antioxidants - metabolism; Basic Research; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cytoskeletal Proteins - genetics; Gene Amplification; Gene Expression; Heme Oxygenase-1 - genetics; Interferon-gamma - metabolism; Interleukin-17 - metabolism; Interleukin-4 - metabolism; Kelch-Like ECH-Associated Protein 1; Lymphocyte Activation - genetics; Membrane Proteins - genetics; Mice; Mice, Knockout; Mice, Transgenic; NAD(P)H Dehydrogenase (Quinone) - genetics; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Oxidative Stress; Reperfusion Injury - complications; Reperfusion Injury - immunology; Reperfusion Injury - pathology; RNA, Messenger - metabolism; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - physiology; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.2014100978

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.