Nuclear factor of activated T cells 5 deficiency increases the severity of neuronal cell death in ischemic injury.

Abstract

Nuclear factor of activated T cells 5 (NFAT5) has been implicated in regulating several genes that are thought to be neuroprotective in ischemic injury. Because of the embryonic lethality of NFAT5 knockout (NFAT5(-/-)) mice, the heterozygous (NFAT5(+/-)) mice were used to study the in vivo role of NFAT5 in hypoxia/ischemia (H/I) condition. The NFAT5(+/-) mice exhibited more severe neurological deficits, larger infarct area and edema formation associated with increased aquaporin 4 expressions in the brain. Under in vitro H/I condition, increased apoptotic cell death was found in NFAT5(-/-) neurons. Moreover, SMIT, a downstream to NFAT5, was upregulated in NFAT5(+/+) neurons, while the SMIT level could not be upregulated in NFAT5(-/-) neurons under H/I condition. The elevation of reactive oxygen species generation in NFAT5(-/-) neurons under H/I condition further confirmed that NFAT5(-/-) neurons were more susceptible to oxidative stress. The present study demonstrated that activation of NFAT5 and its downstream SMIT induction is important in protecting neurons from ischemia-induced oxidative stress.