T lymphocyte-specific activation of Nrf2 protects from AKI

Sanjeev Noel, Maria N. Martina, Samatha Bandapalle, Lorraine C. Racusen, Haranatha R. Potteti, Abdel R.A. Hamad, Sekhar P. Reddy, Hamid Rabb

Research output: Contribution to journalArticlepeer-review

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 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.

Original languageEnglish (US)
Pages (from-to)2989-3000
Number of pages12
JournalJournal of the American Society of Nephrology
Volume26
Issue number12
DOIs
StatePublished - Dec 2015

ASJC Scopus subject areas

  • Nephrology

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