TY - JOUR
T1 - T lymphocyte-specific activation of Nrf2 protects from AKI
AU - Noel, Sanjeev
AU - Martina, Maria N.
AU - Bandapalle, Samatha
AU - Racusen, Lorraine C.
AU - Potteti, Haranatha R.
AU - Hamad, Abdel R.A.
AU - Reddy, Sekhar P.
AU - Rabb, Hamid
N1 - Publisher Copyright:
Copyright © 2015 by the American Society of Nephrology.
PY - 2015/12
Y1 - 2015/12
N2 - 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 IRinduced 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-a, IFN-g, 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.
AB - 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 IRinduced 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-a, IFN-g, 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.
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U2 - 10.1681/ASN.2014100978
DO - 10.1681/ASN.2014100978
M3 - Article
C2 - 26293820
AN - SCOPUS:84949920604
SN - 1046-6673
VL - 26
SP - 2989
EP - 3000
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 12
ER -