Targeted disruption of Nrf2 causes regenerative immune-mediated hemolytic anemia

Lee, Jongmin; Chan, Ka‐Kui; Kan, Yuet Wai; Johnson, Jeffrey A.

doi:10.1073/pnas.0403620101

Cited by 115 publications

(101 citation statements)

References 31 publications

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“…Nrf2 Ϫ/Ϫ mice, lacking the ability to induce ARE-driven gene expression, are more susceptible to a variety of toxic insults in vivo (35,38,59,60). Furthermore, Nrf2 Ϫ/Ϫ mice are known to spontaneously develop hemolytic anemia and a lupus-like syndrome relatively late in life (52,61,62). The wide array of tissues affected by Nrf2 deficiency suggests a strong role in general cellular protection.…”

Section: Discussionmentioning

confidence: 99%

Protection from mitochondrial complex II inhibitionin vitroandin vivoby Nrf2-mediated transcription

Calkins

Jakel

Johnson

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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238

206

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Complex II inhibitors 3-nitropropionic acid (3NP) and malonate cause striatal damage reminiscent of Huntington's disease and have been shown to involve oxidative stress in their pathogenesis. Because nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent transcriptional activation by means of the antioxidant response element is known to coordinate the up-regulation of cytoprotective genes involved in combating oxidative stress, we investigated the significance of Nrf2 in complex II-induced toxicity. We found that Nrf2-deficient cells and Nrf2 knockout mice are significantly more vulnerable to malonate and 3NP and demonstrate increased antioxidant response element (ARE)-regulated transcription mediated by astrocytes. Furthermore, ARE preactivation by means of intrastriatal transplantation of Nrf2-overexpressing astrocytes before lesioning conferred dramatic protection against complex II inhibition. These observations implicate Nrf2 as an essential inducible factor in the protection against complex II inhibitor-mediated neurotoxicity. These data also introduce Nrf2-mediated ARE transcription as a potential target of preventative therapy in neurodegenerative disorders such as Huntington's disease.3-nitropropionic acid ͉ antioxidant response element ͉ astrocytes ͉ malonate M itochondrial complex II inhibition with 3-nitropropionic acid (3NP) or malonate produces a characteristic striatal degeneration similar to that seen in Huntington's disease (HD) (1, 2). HD is an autosomal dominant neurodegenerative disorder that results from a polyglutamine repeat expansion in the first exon of the huntingtin gene (3). Hallmarks of the genetic disease include severe degeneration of striatal medium spiny neurons and progressive choreiform movements (4, 5). Similar behavioral deficits and selective damage to the medium spiny neurons of the striatum with sparing of the aspiny neurons are seen after complex II inhibition (6-10).Furthermore, there is developing evidence that HD pathogenesis involves mitochondrial dysfunction, excitotoxicity, and subsequent reactive oxygen species (ROS) production (11-13). Mitochondrial deficiencies, including reduced overall respiration and reduced activities of complex II, III, and IV, have been measured in the striatum of postmortem HD brains (14,15). Similarly, reduced mitochondrial activity has been observed in at least one genetic mouse model of HD (16), and enhancement of electron transport by coenzyme Q10 is effective in genetic models (17)(18)(19)(20). HD patients also display increased ROS production in red blood cells and the striatum (21-24), which is reflected in in vitro and genetic mouse models of HD (18,(25)(26)(27).Complex II inhibitors generate ROS (26, 27) as a direct consequence of disruption of the electron transport chain and excitotoxicity by means of calcium influx through the N-methyl-D-aspartate receptor (28-30). Additionally, the high concentration of striatal dopamine may contribute to ROS production and exacerbate the damage caused by complex II inhibition (31). Stri...

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Section: Discussionmentioning

confidence: 99%

Protection from mitochondrial complex II inhibitionin vitroandin vivoby Nrf2-mediated transcription

Calkins

Jakel

Johnson

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

238

206

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“…In 1996, Chan et al [24] showed that NRF2 is not essential in developmental processes but later this have been challenged [25][26][27]. SKN-1, the Caenorhabditis elegans ortholog of NRF2, is known to be important in the mesoderm and endoderm formation [28].…”

Section: Functional Analysis Of the Nrf2 Interactomementioning

confidence: 99%

The NRF2‐related interactome and regulome contain multifunctional proteins and fine‐tuned autoregulatory loops

et al. 2012

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a b s t r a c t NRF2 is a well-known, master transcription factor (TF) of oxidative and xenobiotic stress responses. Recent studies uncovered an even wider regulatory role of NRF2 influencing carcinogenesis, inflammation and neurodegeneration. Prompted by these advances here we present a systems-level resource for NRF2 interactome and regulome that includes 289 protein-protein, 7469 TF-DNA and 85 miRNA interactions. As systems-level examples of NRF2-related signaling we identified regulatory loops of NRF2 interacting proteins (e.g., JNK1 and CBP) and a fine-tuned regulatory system, where 35 TFs regulated by NRF2 influence 63 miRNAs that down-regulate NRF2. The presented network and the uncovered regulatory loops may facilitate the development of efficient, NRF2-based therapeutic agents.

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“…The IgG bound to RBCs was assessed for RBC that had been washed with PBS three times followed by incubation with FITC-conjugated rabbit anti-mouse IgG (100 times dilution; Dako) [23].…”

Section: Flow Cytometry Analyses Of Ros and Bound Igg To Rbcsmentioning

confidence: 99%

Elevated oxidative stress in erythrocytes due to a SOD1 deficiency causes anaemia and triggers autoantibody production

Iuchi

Okada

Onuma

et al. 2007

Biochemical Journal

150

105

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Reactive oxygen species are involved in the aging process and diseases. Despite the important role of Cu/Zn SOD (superoxide dismutase) encoded by SOD1, SOD1 −/− mice appear to grow normally under conventional breeding conditions. In the present paper we report on a novel finding showing a distinct connection between oxidative stress in erythrocytes and the production of autoantibodies against erythrocytes in SOD1 −/− mice. Evidence is presented to show that SOD1 is primarily required for maintaining erythrocyte lifespan by suppressing oxidative stress. A SOD1 deficiency led to an increased erythrocyte vulnerability by the oxidative modification of proteins and lipids, resulting in anaemia and compensatory activation of erythropoiesis. The continuous destruction of oxidized erythrocytes appears to induce the formation of autoantibodies against certain erythrocyte components, e.g. carbonic anhydrase II, and the immune complex is deposited in the glomeruli. The administration of an antioxidant, N-acetylcysteine, suppressed erythrocyte oxidation, ameliorated the anaemia, and inhibited the production of autoantibodies. These data imply that a high level of oxidative stress in erythrocytes increases the production of autoantibodies, possibly leading to an autoimmune response, and that the intake of antioxidants would prevent certain autoimmune responses by maintaining an appropriate redox balance in erythrocytes.

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Targeted disruption of Nrf2 causes regenerative immune-mediated hemolytic anemia

Cited by 115 publications

References 31 publications

Protection from mitochondrial complex II inhibitionin vitroandin vivoby Nrf2-mediated transcription

Protection from mitochondrial complex II inhibitionin vitroandin vivoby Nrf2-mediated transcription

The NRF2‐related interactome and regulome contain multifunctional proteins and fine‐tuned autoregulatory loops

Elevated oxidative stress in erythrocytes due to a SOD1 deficiency causes anaemia and triggers autoantibody production

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