Neural Regeneration Research ›› 2022, Vol. 17 ›› Issue (3): 661-672.doi: 10.4103/1673-5374.320991

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Krüppel-like factor 7 attenuates hippocampal neuronal injury after traumatic brain injury

Wen-Yuan Li1, #, Xiu-Mei Fu2, 3, #, Zhen-Dong Wang4, Zhi-Gang Li5, Duo Ma1, Ping Sun1, Gui-Bo Liu1, Xiao-Feng Zhu1, *, Ying Wang1, *   

  1. 1Institute of Neural Tissue Engineering, Mudanjiang Medical University, Mudanjiang, Heilongjiang Province, China; 2Department of Anatomy, College of Basic Medical Sciences, Chengde Medical University, Chengde, Hebei Province, China; 3Hebei Key Laboratory of Nerve Injury and Repair, Chengde Medical University, Chengde, Hebei Province, China; 4Department of Otorhinolaryngology, Mudanjiang City Second People’s Hospital, Mudanjiang, Heilongjiang Province, China; 5The First Department of General Surgery, Hongqi Hospital, Mudanjiang Medical University, Mudanjiang, Heilongjiang Province, China
  • Online:2022-03-15 Published:2021-10-15
  • Contact: Ying Wang, PhD, yingwang2016@sina.com; Xiao-Feng Zhu, PhD, sjkx@sohu.com.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, No. 81870977 (to YW); the Natural Science Foundation of Heilongjiang of China, No. H2018068 (to WYL); the Basic Research Operating Expenses Program of Heilongjiang Provincial Universities of China, No. 2019-KYYWFMY-0018 (to WYL); the Graduate Innovative Research Projects of Mudanjiang Medical College of China, No. YJSCX-MY22 (to DM); Key projects of Education Department of Hebei Province of China, No. ZD2020178 (to XMF); and Hebei Key Laboratory of Nerve Injury and Repair of China (to XMF).

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Abstract: Our previous study has shown that the transcription factor Krüppel-like factor 7 (KLF7) promotes peripheral nerve regeneration and motor function recovery after spinal cord injury. KLF7 also participates in traumatic brain injury, but its regulatory mechanisms remain poorly understood. In the present study, an HT22 cell model of traumatic brain injury was established by stretch injury and oxygen-glucose deprivation. These cells were then transfected with an adeno-associated virus carrying KLF7 (AAV-KLF7). The results revealed that, after stretch injury and oxygen-glucose deprivation, KLF7 greatly reduced apoptosis, activated caspase-3 and lactate dehydrogenase, downregulated the expression of the apoptotic markers B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax) and cleaved caspase-3, and increased the expression of βIII-tubulin and the antiapoptotic marker Bcl-2. Furthermore, KLF7 overexpression upregulated Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) phosphorylation in HT22 cells treated by stretch injury and oxygen-glucose deprivation. Immunoprecipitation assays revealed that KLF7 directly participated in the phosphorylation of STAT3. In addition, treatment with AG490, a selective inhibitor of JAK2/STAT3, weakened the protective effects of KLF7. A mouse controlled cortical impact model of traumatic brain injury was then established. At 30 minutes before modeling, AAV-KLF7 was injected into the ipsilateral lateral ventricle. The protein and mRNA levels of KLF7 in the hippocampus were increased at 1 day after injury and recovered to normal levels at 3 days after injury. KLF7 reduced ipsilateral hippocampal atrophy, decreased the injured cortex volume, downregulated Bax and cleaved caspase-3 expression, and increased the number of 5-bromo-2′-deoxyuridine-positive neurons and Bcl-2 protein expression. Moreover, KLF7 transfection greatly enhanced the phosphorylation of JAK2 and STAT3 in the ipsilateral hippocampus. These results suggest that KLF7 may protect hippocampal neurons after traumatic brain injury through activation of the JAK2/STAT3 signaling pathway. The study was approved by the Institutional Review Board of Mudanjiang Medical University, China (approval No. mdjyxy-2018-0012) on March 6, 2018.

Key words: apoptosis, hippocampus, JAK2/STAT3, Kruppel-like factor 7, neuroprotection, oxygen-glucose deprivation, stretch, traumatic brain injury

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