T Cell Specific Up Regulation of Nrf2 Regulated Antioxidant Response Protects from Kidney Ischemia Reperfusion Injury in Mice
1Department of Medicine, Johns Hopkins University, Baltimore, MD
2Department of Pathology, Johns Hopkins University, Baltimore, MD
3Department of Pediatrics, University of Illinois, Chicago, IL.
Meeting: 2015 American Transplant Congress
Abstract number: D14
Keywords: Ischemia, Oxidant stress, Renal failure, T cells
Session Information
Session Name: Poster Session D: Costimulation and Signaling in Lymphocytes
Session Type: Poster Session
Date: Tuesday, May 5, 2015
Session Time: 5:30pm-6:30pm
Presentation Time: 5:30pm-6:30pm
Location: Exhibit Hall E
Background: T lymphocytes mediate important pathophysiological roles during ischemia reperfusion injury (IRI). Transcription factor Nrf2 is protective during experimental kidney IRI and thought to be operational mainly in the kidney epithelial cells. We, however, hypothesized that Nrf2 regulated antioxidant response in T cells mediates IRI.
Methods: T cell specific augmentation of Nrf2 was achieved by deleting Keap1, the inhibitor of Nrf2, using Cre-LoxP technology. The effect of Keap1 deletion on Nrf2 activity was assessed by measuring Nqo1 and HO-1 gene expression. Kidney IRI was induced by bilateral renal pedicle clamping and serum creatinine (SCr) measured to assess kidney function. Kidneys were assessed for post-ischemic histological changes, infiltrating immune cells and inflammatory cytokines. Adoptive transfer of high Nrf2-T cells into wild type mice was performed to assess clinical translational potential.
Results: T cell specific augmentation of Nrf2 resulted in significant increase in baseline Nqo1 (p=0.01) and HO-1 (p=0.05) mRNA levels in T cells. Mice with high Nrf2-T cell had significantly lower SCr (p=0.01) and fewer necrotic tubules in cortex (p=0.001) and outer medulla (p=0.05) 24h post ischemia as compared to control mice. Kidneys from these mice had an increased frequency of CD25+Foxp3+ regulatory T cells (p=0.01) and decreased frequency of CD11bCD11c (p=0.01) and F4/80 (p=0.01) positive cells among CD45+ cells at baseline. Furthermore T cells with high Nrf2 had an attenuated intracellular TNFα, IFNγ and IL17 levels. Adoptive transfer of high Nrf2-T cells into wild type mice significantly improved kidney function (p=0.02) and survival (χ2=0.01).
Conclusions: These data demonstrate that T cell specific augmentation of Nrf2 regulated antioxidant response protects from IRI. Enhanced antioxidant response in T cells can provide a novel immune cell based therapeutic to kidney IRI as well as to IRI of other organs, and may also be useful for allograft rejection.
To cite this abstract in AMA style:
Noel S, Martina M, Bandapalle S, Reddy S, Racusen L, Hamad A, Rabb H. T Cell Specific Up Regulation of Nrf2 Regulated Antioxidant Response Protects from Kidney Ischemia Reperfusion Injury in Mice [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/t-cell-specific-up-regulation-of-nrf2-regulated-antioxidant-response-protects-from-kidney-ischemia-reperfusion-injury-in-mice/. Accessed May 19, 2025.« Back to 2015 American Transplant Congress