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

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

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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-1α, 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-1α 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-1α, while HIF-1α antisense oligonucleotide exhibited little effect on the expression of CREB. However, HIF-1α antisense oligonucleotide administration did effectively suppress the expression of VEGF. Our results of the chromosome immunoprecipitation also indicated that HIF-1α 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-1α upregulation, and finally leads to the stimulation of VEGF expression and the induction of neurogenesis.

Original languageEnglish
Pages (from-to)1651-1661
Number of pages11
JournalPflugers Archiv European Journal of Physiology
Volume467
Issue number8
DOIs
Publication statusPublished - Aug 24 2015

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Phosphorylation
Neurogenesis
Brain
Vascular Endothelial Growth Factor A
Antisense Oligonucleotides
Up-Regulation
Symporters
Traumatic Brain Injury
Chromatin Immunoprecipitation
Mitogen-Activated Protein Kinase Kinases
Chromosomes
Immunoprecipitation
Labeling
Chromatin
Hippocampus
Genes
Fluorescence
Western Blotting
Chemical activation
Morbidity

Keywords

  • CREB
  • Hippocampus
  • Neurogenesis
  • NKCC1
  • TBI

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Physiology (medical)

Cite this

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

In: Pflugers Archiv European Journal of Physiology, Vol. 467, No. 8, 24.08.2015, p. 1651-1661.

Research output: Contribution to journalArticle

Lu, KT, Huang, TC, Wang, JY, You, YS, Chou, JL, Chan, MWY, Wo, PYY, Amstislavskaya, TG, Tikhonova, MA & Yang, YL 2015, 'NKCC1 mediates traumatic brain injury-induced hippocampal neurogenesis through CREB phosphorylation and HIF-1α expression', Pflugers Archiv European Journal of Physiology, vol. 467, no. 8, pp. 1651-1661. https://doi.org/10.1007/s00424-014-1588-x
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. / NKCC1 mediates traumatic brain injury-induced hippocampal neurogenesis through CREB phosphorylation and HIF-1α expression. In: Pflugers Archiv European Journal of Physiology. 2015 ; Vol. 467, No. 8. pp. 1651-1661.
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AU - Lu, Kwok Tung

AU - Huang, Tai Chun

AU - Wang, Jia Yi

AU - You, Ya Shen

AU - Chou, Jian Liang

AU - Chan, Michael W Y

AU - Wo, Peter Y Y

AU - Amstislavskaya, Tamara G.

AU - Tikhonova, Maria A.

AU - Yang, Yi Ling

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N2 - 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-1α, 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-1α 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-1α, while HIF-1α antisense oligonucleotide exhibited little effect on the expression of CREB. However, HIF-1α antisense oligonucleotide administration did effectively suppress the expression of VEGF. Our results of the chromosome immunoprecipitation also indicated that HIF-1α 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-1α upregulation, and finally leads to the stimulation of VEGF expression and the induction of neurogenesis.

AB - 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-1α, 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-1α 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-1α, while HIF-1α antisense oligonucleotide exhibited little effect on the expression of CREB. However, HIF-1α antisense oligonucleotide administration did effectively suppress the expression of VEGF. Our results of the chromosome immunoprecipitation also indicated that HIF-1α 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-1α upregulation, and finally leads to the stimulation of VEGF expression and the induction of neurogenesis.

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