BDNF-mediated mitophagy alleviates high-glucose-induced brain microvascular endothelial cell injury

Abstract

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.

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Abbreviations

BDNF:

Brain-derived neurotrophic factor

BMECs:

Brain microvascular endothelial cells

mPTP:

Mitochondrial permeability transition pore

LC3-II:

Microtubule-associated protein 1 light chain 3B

p62:

SQSTM1

TOMM20:

Translocase of outer mitochondrial membrane 20

HIF-1α:

Hypoxia-inducible factor-1α

TrkB:

Tropomyosin receptor or kinase B

BNIP3:

BCL2/adenovirus E1B 19 kDa protein-interacting protein 3

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Acknowledgements

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).

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Correspondence to Hong Jin.

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Jin, H., Zhu, Y., Li, Y. et al. BDNF-mediated mitophagy alleviates high-glucose-induced brain microvascular endothelial cell injury. Apoptosis 24, 511–528 (2019). https://doi.org/10.1007/s10495-019-01535-x

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Keywords

  • BDNF
  • BMECs
  • Hyperglycemia
  • Mitochondrial function
  • Mitophagy