Altered blood–brain barrier integrity in adult aquaporin-4 knockout mice

Zhou, Jianping; Kong, Hui; Hua, Xin; Xiao, Ming; Ding, Jiong; Hu, Gang

doi:10.1097/wnr.0b013e3282f2b4eb

Cited by 124 publications

(104 citation statements)

References 18 publications

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“…As AQP4 is known to regulate water fluxes in the brain, it was likely that this altered expression would influence BBB permeability. Accordingly, altered BBB integrity associated with hyperpermeability has been observed in AQP4 knockout mice (6). To directly test this hypothesis, we cultured HFAs and BBB-ECs on alternate sides of a Boyden chamber membrane and found that NMO-IgG-containing sera induce a significant increase in BBB permeability.…”

Section: Discussionmentioning

confidence: 98%

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Functional Consequences of Neuromyelitis Optica-IgG Astrocyte Interactions on Blood-Brain Barrier Permeability and Granulocyte Recruitment

Vincent

Saikali

Cayrol

et al. 2008

The Journal of Immunology

218

175

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Autoantibody neuromyelitis optica-IgG (NMO-IgG) recognizing aquaporin-4 (AQP4) is implicated as playing a central role in the physiopathology of NMO. The aim of this in vitro-based study was to characterize functional consequences of interaction between NMO-IgG and cells of the neurovascular unit (astrocytes and brain endothelium) that would provide insight into recognized features of NMO, namely altered blood-brain barrier (BBB) permeability and granulocyte recruitment. We used sera from NMO and longitudinally extensive transverse myelitis cases shown to bind in a characteristic perivascular pattern to primate cerebellar slices. Using flow cytometry, we found that sera from NMO-IgG-positive patients reacted with CNS-derived human fetal astrocytes, whereas sera from multiple sclerosis patients did not. We demonstrated that NMO-IgG binding to astrocytes alters aquaporin-4 polarized expression and increases permeability of a human BBB endothelium/astrocyte barrier. We further demonstrated that NMO-IgG binding to human fetal astrocytes can result in NK cell degranulation, astrocyte killing by Ab-dependent cellular cytotoxicity and complement-dependent granulocyte attraction through the BBB model. Our study highlights important functional roles for NMO-IgG that could account for pathological lesions and BBB dysfunction observed in NMO.

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Section: Discussionmentioning

confidence: 98%

“…AQP4 is mainly expressed on astrocyte end-feet at the bloodbrain barrier (BBB) and brain-cerebrospinal fluid barrier (4). Analyses of AQP4-deficient mice revealed its involvement in cerebral water and ion homeostasis regulation, astrocyte migration, neural signal transduction, and demonstrated its role for the maintenance of BBB integrity (5,6).…”

mentioning

confidence: 99%

Functional Consequences of Neuromyelitis Optica-IgG Astrocyte Interactions on Blood-Brain Barrier Permeability and Granulocyte Recruitment

Vincent

Saikali

Cayrol

et al. 2008

The Journal of Immunology

218

175

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“…8 As AQP4 is highly concentrated in the area of the BBB, it is believed to have important roles in maintaining BBB integrity throughout development and in mature individuals. 9,10 Furthermore, our previous study shows that AQP4 deletion resulted in more serious disruption of BBB in morphology and function after ICH. 11 It has been reported that upregulation of AQP4 expression is observed in hypoxic-ischemic neonatal rats after receiving EPO.…”

mentioning

confidence: 97%

“…8 As AQP4 is highly concentrated in the area of the BBB, it is believed to have important roles in maintaining BBB integrity throughout development and in mature individuals. 9,10 …”

mentioning

confidence: 99%

Erythropoietin protects against hemorrhagic blood–brain barrier disruption through the effects of aquaporin-4

Chu

Ding

Tang

et al. 2014

Laboratory Investigation

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Erythropoietin (EPO) has protective effects against many neurological diseases, including intracerebral hemorrhage (ICH). Here, we aimed to test EPO's effects on blood-brain barrier (BBB) disruption morphologically and functionally following ICH, which has not been well investigated. We also examined whether the effects were dependent on aquaporin-4 (AQP4). We detected the expression of perihematomal AQP4 and EPO receptor (EPOR) induced by EPO injection at 1, 3 and 7 days after ICH. We also examined the effects of EPO on BBB disruption by ICH in wild-type mice, and tested whether such effects were AQP4 dependent by using AQP4 knock-out mice. Furthermore, we assessed the related signal transduction pathways via astrocyte cultures. We found that EPO highly increased perihematomal AQP4 and EPOR expression. Specifically, EPO led to BBB protection in both types of mice by functionally reducing brain edema and BBB permeability, as well as morphologically suppressing tight junction (TJ) opening and endothelial cell swelling, and increasing expression of the TJ proteins occludin and zonula occluden-1 (ZO-1). Statistical analysis indicated that AQP4 was required for these effects. In addition, EPO upregulated phosphorylation of C-Jun amino-terminal kinase (JNK) and p38-mitogenactivated protein kinase (MAPK) as well as EPOR and AQP4 proteins in cultured astrocytes. The latter was inhibited by JNK and p38-MAPK inhibitors. Our data suggest that EPO protects BBB from disruption after ICH and that the main targets are the TJ proteins occludin and ZO-1. The effects of EPO are associated with increased levels of AQP4, and may occur through activation of JNK and p38-MAPK pathways after binding to EPOR. Erythropoietin (EPO) was originally recognized as a humoral mediator involved in the maturation and proliferation of erythroid progenitor cells but is now appreciated for its neuroprotective effects in the central nervous system (CNS) as well. There has been a great deal of research confirming the protective effect of EPO in cerebral ischemic models, the mechanisms of which include apoptosis reduction, inflammation inhibition, angiogenesis enhancement and cerebral blood flow restoration. 1,2 In recent years, studies have been conducted to determine EPO's effects on intracerebral hemorrhage (ICH), another type of stroke. 3,4 However, the mechanisms involved need further investigation.Disruption of the blood-brain barrier (BBB) is an important pathophysiological change after ICH and contributes to vasogenic brain edema formation, which is often serious and leads to poor prognosis. Previous research on EPO and BBB mainly focused on cerebral ischemic models, indicating that BBB disruption induced by middle cerebral artery occlusion can be attenuated by EPO. 5,6 So far, there has only been one study describing how EPO acts on BBB disruption resulting from ICH, and this study reveals that EPO decreased BBB permeability at 3 days after ICH. 7 However, this effect was observed for only one isolated time point without dynamic observation a...

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“…Notably, these Aqp4 -/-animals are reported to show structural brain abnormalities, including altered BBB integrity (460). Such abnormalities are not in line with other studies on Aqp4 knockout animals (292,311,312).…”

Section: Selective Vulnerability Mediated By the Glial Microenvironmementioning

confidence: 55%

Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson's disease

et al. 2011

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Altered blood–brain barrier integrity in adult aquaporin-4 knockout mice

Cited by 124 publications

References 18 publications

Functional Consequences of Neuromyelitis Optica-IgG Astrocyte Interactions on Blood-Brain Barrier Permeability and Granulocyte Recruitment

Functional Consequences of Neuromyelitis Optica-IgG Astrocyte Interactions on Blood-Brain Barrier Permeability and Granulocyte Recruitment

Erythropoietin protects against hemorrhagic blood–brain barrier disruption through the effects of aquaporin-4

Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson's disease

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