Blood-brain barrier disruption in diabetic mice is linked to Nrf2 signaling deficits: Role of ABCB10?

• Published in: Neuroscience letters Vol. 653; pp. 152 - 158
• Main Authors: Sajja, Ravi K., Prasad, Shikha, Tang, Suni, Kaisar, Mohammad A., Cucullo, Luca
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 13.07.2017
• Subjects: ABCB10; Animals; ATP-Binding Cassette Transporters - metabolism; Blood-Brain Barrier - metabolism; Cells, Cultured; db/db mice; Diabetes Mellitus, Experimental - metabolism; Endothelial Cells - metabolism; Humans; In vivo imaging; Leukocyte; Male; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; NF-E2-Related Factor 2 - metabolism; Oxidative stress; Oxidative stress; Mitochondria; ABCB10; db/db mice; Leukocyte; In vivo imaging
• ISSN: 0304-3940; 1872-7972; 1872-7972
• DOI: 10.1016/j.neulet.2017.05.059

•In vivo fluorescence imaging revealed BBB hyper-permeability in diabetic mice.•Nrf2 is significantly down-regulated in diabetic brain.•Nrf2 regulates mitochondrial ABCB10 expression in human BBB endothelium.•Hyperglycemia markedly reduces ABCB10 expression in BBB endothelial cells.•Nrf2 or ABCB10 gene silencing increases BBB endothelial-monocyte adhesion. Blood-brain barrier (BBB) damage is a critical neurovascular complication of diabetes mellitus that adversely affects the CNS health and function. Previously, we showed the protective role of NF-E2 related factor-2 (Nrf2), a redox sensitive transcription factor, in regulation of BBB integrity. Given the pathogenic role of mitochondrial oxidative stress in diabetes-related microvascular complications, we focused on assessing: 1) the impact of diabetes on brain Nrf2 in correlation with BBB permeability and 2) Nrf2-dependent regulation of the mitochondrial transporter ABCB10, an essential player in mitochondrial function and redox balance at BBB endothelium. Using live animal fluorescence imaging, we demonstrated a strong increase in BBB permeability to 70kDa dextran in db/db diabetic mice that correlated with significant down-regulation of brain Nrf2 protein. Further, Nrf2 gene silencing in human BBB endothelial cells markedly suppressed ABCB10 protein, while Nrf2 activation by sulforaphane up-regulated ABCB10 expression. Interestingly, ABCB10 knockdown resulted in a strong-induction of Nrf2 driven anti-oxidant responses as evidenced by increased expression of Nrf2 and its downstream targets. Nrf2 or ABCB10 silencing elevated endothelial-monocyte adhesion suggesting an activated inflammatory cascade. Thus, our results demonstrate a novel mechanism of ABCB10 regulation driven by Nrf2. In summary, Nrf2 dysregulation and ABCB10 suppression could likely mediate endothelial oxidative/inflammatory stress and BBB disruption in diabetic subjects.