Transcription factor tonicity-responsive enhancer-binding protein (tonebp) which transactivates osmoprotective genes is expressed and upregulated following acute systemic hypertonicity in neurons in brain

Loyher, M.L; Mutin, M; Woo, Seung Kyoon; Kwon, H. Moo; Tappaz, Marcel

doi:10.1016/j.neuroscience.2003.10.025

Cited by 60 publications

(73 citation statements)

References 40 publications

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“…Thus, as expected, complete loss of NFAT5 function results in marked atrophy of the renal medulla (14). However, NFAT5 protein also is expressed in the thymus (7,15), brain (16,17), and liver (16), and is induced upon activation of quiescent T lymphocytes (7) and expressed in various tissues of the developing embryo (18). These observations give rise to the hypothesis that the NFAT5 osmotic stress response pathway plays a critical role in enabling mammalian cells to adapt to osmotic stress that occurs physiologically in tissues other than the kidney.…”

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confidence: 62%

NFAT5/TonEBP mutant mice define osmotic stress as a critical feature of the lymphoid microenvironment

Liu

Roti

et al. 2004

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

255

305

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Osmotic stress responses are critical not only to the survival of unicellular organisms but also to the normal function of the mammalian kidney. However, the extent to which cells outside the kidney rely on osmotic stress responses in vivo remains unknown. Nuclear factor of activated T cells 5 (NFAT5)͞tonicity enhancer binding protein (TonEBP), the only known osmosensitive mammalian transcription factor, is expressed most abundantly in the thymus and is induced upon lymphocyte activation. Here we report that NFAT5͞TonEBP is not only essential for normal cell proliferation under hyperosmotic conditions but also necessary for optimal adaptive immunity. Targeted deletion of exons 6 and 7 of the Nfat5 gene, which encode a critical region of the DNA-binding domain, gave rise to a complete loss of function in the homozygous state and a partial loss of function in the heterozygous state. Complete loss of function resulted in late gestational lethality. Furthermore, hypertonicity-induced NFAT5͞TonEBP transcriptional activity and hsp70.1 promoter function were completely eliminated, and cell proliferation under hyperosmotic culture conditions was markedly impaired. Partial loss of NFAT5͞TonEBP function resulted in lymphoid hypocellularity and impaired antigen-specific antibody responses in viable heterozygous animals. In addition, lymphocyte proliferation ex vivo was reduced under hypertonic, but not isotonic, culture conditions. Direct measurement of tissue osmolality further revealed lymphoid tissues to be hyperosmolar. These results indicate that lymphocyte-mediated immunity is contingent on adaptation to physiologic osmotic stress, thus providing insight into the lymphoid microenvironment and the importance of the NFAT5͞TonEBP osmotic stress response pathway in vivo.

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confidence: 62%

NFAT5/TonEBP mutant mice define osmotic stress as a critical feature of the lymphoid microenvironment

Liu

Roti

et al. 2004

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

255

305

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“…Previous studies showed that the transcription of AR is regulated by osmotic response element binding protein (TonEBP/NFAT5/OREBP), a transcription factor, which also regulates transcription of several ischemic injury-related genes, such as HSP70, SMIT, and TNFa (Lopez-Rodriguez et al, 2001;Rim et al, 1998;Woo et al, 2002). The fact that TonEBP/ NFAT5/OREBP is significantly expressed in neurons and some glial cells suggests that nerve cells can accumulate compatible osmolytes (Loyher et al, 2004) by changing their expression level or translocation. It is possible that the flux through the polyol pathway can lead to elevation of intracellular sorbitol and therefore increasing intracellular hyperosmotic pressure, drawing more water into neurons, and resulting in an increased cytotoxic edema; thereby contributing to larger infarct in GET-1 brains after MCAO.…”

Section: Discussionmentioning

confidence: 99%

Deletion of Aldose Reductase Leads to Protection against Cerebral Ischemic Injury

Cheung

Hung

et al. 2007

J Cereb Blood Flow Metab

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Previously, we reported that transgenic mice overexpressing endothelin-1 in astrocytes showed more severe neurological deficits and increased infarct after transient focal ischemia. In those studies, we also observed increased level of aldose reductase (AR), the first and rate-limiting enzyme of the polyol pathway, which has been implicated in osmotic and oxidative stress. To further understand the involvement of the polyol pathway, the mice with deletion of enzymes in the polyol pathway, AR, and sorbitol dehydrogenase (SD), which is the second enzyme in this pathway, were challenged with similar cerebral ischemic injury. Deletion of AR-protected animals from severe neurological deficits and large infarct, whereas similar protection was not observed in mice with SD deficiency. Most interestingly, AR À/À brains showed lowered expression of transferrin and transferrin receptor with less iron deposition and nitrotyrosine accumulation. The protection against oxidative stress in AR À/À brain was also associated with less poly(adenosine diphosphate-ribose) polymerase (PARP) and caspase-3 activation. Pharmacological inhibition of AR by Fidarestat also protected animals against cerebral ischemic injury. These findings are the first to show that AR contributes to iron-and transferrin-related oxidative stress associated with cerebral ischemic injury, suggesting that inhibition of AR but not SD may have therapeutic potential against cerebral ischemic injury.

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“…14 Particularly in the brain, TonEBP is predominantly expressed in the nuclei of neurons, 15,16 and neurons are more susceptible in seizure-induced death compared with glia. However, inflammatory roles of neuronal TonEBP on pathology of seizures are not known yet.…”

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confidence: 99%

“…16,17 Although the physiological roles of TonEBP have been investigated in the rat brain following systemic hypertonicity, 15,16 not many studies are done considering TonEBP as a transcriptional factor of modulating pathology of neurological diseases. Recently, it has been reported that TonEBP is necessary for transcriptional regulation of aquaporin 4 (AQP4) for astrocytic swelling in kainic acid (KA)-treated hippocampus, and TonEBP-targeted silencing reduced AQP4 expression in primary astrocytes.…”

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confidence: 99%

Tonicity-responsive enhancer binding protein haplodeficiency attenuates seizure severity and NF-κB-mediated neuroinflammation in kainic acid-induced seizures

et al. 2014

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Kainic acid (KA)-induced seizures followed by neuronal death are associated with neuroinflammation and blood-brain barrier (BBB) leakage. Tonicity-responsive enhancer binding protein (TonEBP) is known as a transcriptional factor activating osmoprotective genes, and in brain, it is expressed in neuronal nuclei. Thus dysregulation of TonEBP may be involved in the pathology of KA-induced seizures. Here we used TonEBP heterozygote ( þ / À ) mice to study the roles of TonEBP. Electroencephalographic study showed that TonEBP ( þ / À ) mice reduced seizure frequency and severity compared with wild type during KA-induced status epilepticus. Immunohistochemistry and western blotting analysis showed that KA-induced neuroinflammation and BBB leakage were dramatically reduced in TonEBP ( þ / À ) mice. Similarly, TonEBP-specific siRNA reduced glutamate-induced death in HT22 hippocampal neuronal cells. TonEBP haplodeficiency prevented KA-induced nuclear translocation of NF-jB p65 and attenuated inflammation. Our findings identify TonEBP as a critical regulator of neuroinflammation and BBB leakage in KA-induced seizures, which suggests TonEBP as a good therapeutic target.

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Transcription factor tonicity-responsive enhancer-binding protein (tonebp) which transactivates osmoprotective genes is expressed and upregulated following acute systemic hypertonicity in neurons in brain

Cited by 60 publications

References 40 publications

NFAT5/TonEBP mutant mice define osmotic stress as a critical feature of the lymphoid microenvironment

NFAT5/TonEBP mutant mice define osmotic stress as a critical feature of the lymphoid microenvironment

Deletion of Aldose Reductase Leads to Protection against Cerebral Ischemic Injury

Tonicity-responsive enhancer binding protein haplodeficiency attenuates seizure severity and NF-κB-mediated neuroinflammation in kainic acid-induced seizures

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