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.

<b><i>Aralia elata</i></b> Prevents Neuronal Death by Downregulating Tonicity Response Element Binding Protein in Diabetic Retinopathy

“…For example, TonEBP reportedly contributes to the pathogenesis of diabetic complications, especially diabetic nephropathy [13] . Furthermore, TonEBP is not only essential for neuronal adaptation to hypertonic conditions but is also vital for regulating the transcription of genes to protect neurons against ischemiainduced neuronal death [36] . A recent manuscript identified TonEBP as an essential transcription factor for the regulation of osmotic homeostasis and showed that TonEBP is upregulated in the hyperglycemic diabetesdamaged retina [13] .…”

NFAT5 Has a Job in the Brain

“…NFAT5 also had various roles in the CNS, such as regulating the expression of AQP4 in astrocytes [13], protecting neurons and astrocytes against ischemic damage [14, 33], and participating in neuroinflammation [16]. …”

“…2), although its function is not well understood because of insufficient studies in this area. Besides its classic role in osmotic protection, NFAT5 attenuates the severity of neuronal cell death, infarct area, and edema formation in ischemic injury [14, 15]. It also influences dopaminergic neurotransmission [59] and the action of potential firing of superior cervical ganglion neurons by mediating SMIT1 and KCNQ2/3 [60].…”

“…It is highly expressed in the nuclei of neurons in the fetal and adult brains. It also attenuates the severity of neuronal cell death, infarct area, and edema formation in ischemic injury [14, 15]. In some pathological conditions, the expression level of NFAT5 changes significantly in glial cells.…”

“…Moreover, its expression levels also vary within the individual parts within one limited brain region [12]. Similar to its expression, functions of NFAT5 were quite diverse in neurons, astrocytes, microglia, and other cell types in the central nervous system (CNS), including regulating the expression of AQP4 in astrocytes [13], protecting neurons against ischemic damage [14, 15], and participating in neuroinflammation [16]. The regulation of NFAT5 is also complicated.…”