NKCC1 mediates traumatic brain injury-induced hippocampal neurogenesis through CREB phosphorylation and HIF-1 alpha expression

作者：Lu Kwok Tung; Huang Tai Chun; Wang Jia Yi; You Ya Shen; Chou Jian Liang; Chan Michael W Y; Wo Peter Y Y; Amstislavskaya Tamara G; Tikhonova Maria A; Yang Yi Ling^*

来源：Pflugers Archiv-European Journal of Physiology, 2015, 467(8): 1651-1661.

DOI：10.1007/s00424-014-1588-x

• TBI
• Neurogenesis
• NKCC1
• CREB
• Hippocampus

Traumatic brain injury (TBI) is one of the most prevalent causes of worldwide mortality and morbidity. We previously had evidenced that TBI induced Na-K-2Cl co-transporter (NKCC1) upregulation in hippocampus. Here, we aim to investigate the role of NKCC1 in TBI-induced neurogenesis and the detailed mechanisms. The TBI-associated alternations in the expression of NKCC1, HIF-1 alpha, VEGF, MAPK cascade, and CREB phosphorylation were analyzed by Western blot. TBI-induced neurogenesis was determined by immuno-fluorescence labeling. Chromatin immunoprecipitation was used to elucidate whether HIF-1 alpha would activate VEGF gene after TBI. We found that the level of hippocampal NKCC1 and VEGF began to rise 8 h after TBI, and both of them reached maxima at day 7. Along with the upregulation of NKCC1 and VEGF, MAPK cascade was activated and hippocampal neurogenesis was promoted. Administration of CREB antisense oligonucleotide significantly attenuated the expression of HIF-1 alpha, while HIF-1 alpha antisense oligonucleotide exhibited little effect on the expression of CREB. However, HIF-1 alpha antisense oligonucleotide administration did effectively suppress the expression of VEGF. Our results of the chromosome immunoprecipitation also indicated that HIF-1 alpha could directly act on the VEGF promoter and presumably would elevate the VEGF expression after TBI. All these results have illustrated the correlation between NKCC1 upregulation and TBI-associated neurogenesis. The pathway involves the activation of Raf/MEK/ERK cascade, CREB phosphorylation, and HIF-1 alpha upregulation, and finally leads to the stimulation of VEGF expression and the induction of neurogenesis.

• 出版日期2015-8