BDNF-mediated mitophagy alleviates high-glucose-induced brain microvascular endothelial cell injury
Endothelial cell dysfunction and diabetic vascular complications are intrinsically linked. Although BDNF plays a protective role in cerebral microvascular complications caused by diabetes, the mechanisms of this activity are not fully clear. In this study, we investigated the role of BDNF in the hyperglycemic injury of BMECs and its associated intracellular signal transduction pathways. BMECs were treated with 33 mM glucose to imitate the endothelium under hyperglycemic conditions. The high-glucose treatment caused cell dysfunction, as evaluated by oxidative stress and cell apoptosis, which could be alleviated by BDNF. In addition, BDNF preserved mitochondrial function as assessed by mPTP opening, mitochondrial membrane potential, calcium content, and mitochondrial biogenesis markers. Western blot analysis of LC3-II, p62, and TOMM20 and the detection of mRFP-GFP-LC3 adenovirus for autophagy flux revealed that BDNF enhanced autophagy flux. Furthermore, BDNF activated mitophagy, which was confirmed by the observed colocalization of LC3-II with BNIP3 and from transmission electron microscopy observations. The HIF-1α/BNIP3 signaling pathway was associated with BDNF/TrkB-induced mitophagy. In addition, BDNF-induced mitophagy played a protective role against BMEC damage under hyperglycemia. Thus, the results of this study suggest that BDNF/TrkB/HIF-1α/BNIP3-mediated mitophagy protects BMECs from hyperglycemia.
KeywordsBDNF BMECs Hyperglycemia Mitochondrial function Mitophagy
Brain-derived neurotrophic factor
Brain microvascular endothelial cells
Mitochondrial permeability transition pore
Microtubule-associated protein 1 light chain 3B
Translocase of outer mitochondrial membrane 20
Tropomyosin receptor or kinase B
BCL2/adenovirus E1B 19 kDa protein-interacting protein 3
This work was supported by the Fundamental Research Funds for the Central Universities and Postgraduate Research & Practice Innovation Program of Jiangsu Province (No. KYCX17_0174) and the Jiangsu Provincial Health and Wellness Committee Research Project (No. H2018001).
Compliance with ethical standards
Conflict of interest
The authors have no conflicts of interest.
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