Abstract
Hypoxic-ischemic encephalopathy (HIE) is a serious birth complication with severe long-term sequelae such as cerebral palsy, epilepsy and cognitive disabilities. Na+-K+-2Cl– cotransporters 1 (NKCC1) is dramatically upregulated after hypoxia-ischemia (HI), which aggravates brain edema and brain damage. Clinically, an NKCC1-specific inhibitor, bumetanide, is used to treat diseases related to aberrant NKCC1 expression, but the underlying mechanism of aberrant NKCC1 expression has rarely been studied in HIE. In this study, the cooperative effect of hypoxia-inducible factor-1α (HIF-1α) and nuclear factor of activated T cells 5 (NFAT5) on NKCC1 expression was explored in hippocampal neurons under hypoxic conditions. HI increased HIF-1α nuclear localization and transcriptional activity, and pharmacological inhibition of the HIF-1α transcription activity or mutation of hypoxia responsive element (HRE) motifs recovered the hypoxia-induced aberrant expression and promoter activity of NKCC1. In contrast, oxygen–glucose deprivation (OGD)-induced downregulation of NFAT5 expression was reversed by treating with hypertonic saline, which ameliorated aberrant NKCC1 expression. More importantly, knocking down NFAT5 or mutation of the tonicity enhancer element (TonE) stimulated NKCC1 expression and promoter activity under normal physiological conditions. The positive regulation of NKCC1 by HIF-1α and the negative regulation of NKCC1 by NFAT5 may serve to maintain NKCC1 expression levels, which may shed light on the transcription regulation of NKCC1 in hippocampal neurons after hypoxia.
Highlights
Newborns with hypoxic-ischemic encephalopathy (HIE) usually have loss of hippocampal neurons (Arriaga-Redondo et al, 2019) and aberrant hippocampal neurogenesis (Mattiesen et al, 2009; Hu et al, 2017)
Our previous research showed that Na+K+-2Cl− cotransporters 1 (NKCC1) was a potential target for HIE therapy, its ab-normal expression induces aberrant hippocampal neurogenesis and blood-brain barrier (BBB) leakage (Hu et al, 2017; Luo et al, 2018)
Our previous research showed that inhibition of NKCC1 expression reduced neonatal HI-induced seizure susceptibility via lessening aberrant hippocampal neurogenesis and BBB leakage by rescuing the expression of tight junction-related protein zona occludens-1 (ZO-1) in endothelial cells (Hu et al, 2017; Luo et al, 2018)
Summary
Newborns with hypoxic-ischemic encephalopathy (HIE) usually have loss of hippocampal neurons (Arriaga-Redondo et al, 2019) and aberrant hippocampal neurogenesis (Mattiesen et al, 2009; Hu et al, 2017). NKCC1 (encoded by SLC12A2) belongs to the subfamily of cation-chloride cotransporters that are involved in cell volume and intracellular Cl− concentration ([Cl−]i) regulation (Watanabe and Fukuda, 2015). Glia, endothelial cells and epithelial cells that line the brain’s ventricular system regulate [Cl−]i to help maintain their cellular volume amidst changes of extracellular osmolality and intracellular solute content (Simard et al, 2010). Bumetanide, an NKCC1-specific inhibitor, is used to treat aberrant NKCC1 expression related diseases (Kahle and Staley, 2008; Kharod et al, 2019)
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