Recombinant FGF21 Protects Against Blood-Brain Barrier Leakage Through Nrf2 Upregulation in Type 2 Diabetes Mice

Blood-brain barrier (BBB) damage is a characteristic feature of diabetes mellitus pathology and plays significant roles in diabetes-associated neurological disorders. However, effective treatments for diabetes targeting BBB damage are yet to be developed. Fibroblast growth factor 21 (FGF21) is a pot...

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Published in:Molecular neurobiology Vol. 56; no. 4; pp. 2314 - 2327
Main Authors: Yu, Zhanyang, Lin, Li, Jiang, Yinghua, Chin, Ian, Wang, Xiaojie, Li, Xiaokun, Lo, Eng H., Wang, Xiaoying
Format: Journal Article
Language:English
Published: New York Springer US 01.04.2019
Springer Nature B.V
Subjects:
Animals
Biomedical and Life Sciences
Biomedicine
Blood-brain barrier
Blood-Brain Barrier - drug effects
Blood-Brain Barrier - pathology
Brain injury
Cell Biology
Cell Membrane Permeability - drug effects
Cells, Cultured
Diabetes
Diabetes mellitus
Diabetes mellitus (non-insulin dependent)
Diabetes Mellitus, Experimental - drug therapy
Diabetes Mellitus, Experimental - genetics
Diabetes Mellitus, Type 2 - drug therapy
Diabetes Mellitus, Type 2 - genetics
Drug development
Endothelial cells
Endothelial Cells - drug effects
Endothelial Cells - metabolism
Fibroblast growth factor receptor 1
Fibroblast Growth Factors - pharmacology
Fibroblast Growth Factors - therapeutic use
Glucose metabolism
Humans
Hyperglycemia
Hyperglycemia - pathology
Interleukin 1
Interleukin-1beta - metabolism
Kelch-Like ECH-Associated Protein 1 - metabolism
Lipid metabolism
Male
Membrane permeability
Mice
Microvasculature
Models, Biological
Neurobiology
Neurological diseases
Neurology
Neurosciences
NF-E2-Related Factor 2 - genetics
NF-E2-Related Factor 2 - metabolism
Permeability
Protein Binding - drug effects
Proteins
Recombinant Proteins - pharmacology
Recombinant Proteins - therapeutic use
Signal Transduction - drug effects
Up-regulation
Up-Regulation - drug effects
Hyperglycemia
Nrf2
Fibroblast growth factor 21 (FGF21)
Blood-brain barrier (BBB)
Keap1
Inflammation
Diabetes
FGFR1
ISSN:0893-7648, 1559-1182, 1559-1182
Online Access:Get full text
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Summary:Blood-brain barrier (BBB) damage is a characteristic feature of diabetes mellitus pathology and plays significant roles in diabetes-associated neurological disorders. However, effective treatments for diabetes targeting BBB damage are yet to be developed. Fibroblast growth factor 21 (FGF21) is a potent regulator of lipid and glucose metabolism. In this study, we tested the hypothesis that recombinant FGF21 (rFGF21) administration may reduce type 2 diabetes (T2D)-induced BBB disruption via NF-E2-related factor-2 (Nrf2) upregulation. Our experimental results show that rFGF21 treatment significantly ameliorated BBB permeability and preserved junction protein expression in db/db mice in vivo. This protective effect was further confirmed by ameliorated transendothelial permeability and junction protein loss by rFGF21 under hyperglycemia and IL1β (HG-IL1β) condition in cultured human brain microvascular endothelial cells (HBMEC) in vitro. We further reveal that rFGF21 can activate FGF receptor 1 (FGFR1) that increases its binding with Kelch ECH-associating protein 1 (Keap1), a repressor of Nrf2, thereby reducing Keap1-Nrf2 interaction leading to Nrf2 release. These data suggest that rFGF21 administration may decrease T2D-induced BBB permeability, at least in part via FGFR1-Keap1-Nrf2 activation pathway. This study may provide an impetus for development of therapeutics targeting BBB damage in diabetes.
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ISSN:0893-7648
1559-1182
1559-1182
DOI:10.1007/s12035-018-1234-2