Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 501, Issue 4, Pages 1048-1054Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2018.05.106
Keywords
Lipid mediator; Lysophospholipid; Neurological diseases; GPCR; ROCK; p2ry5
Categories
Funding
- Ministry of Education, Science, Culture, Sports and Technology of Japan [19002011]
- NIH [R01NS103940]
- Research Fellowships of Japanese Society for the Promotion of Science [07J01750, 07J05298]
- Grants-in-Aid for Scientific Research [07J05298, 19002011, 07J01750] Funding Source: KAKEN
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Cerebral edema is a life-threatening neurological condition characterized by brain swelling due to the accumulation of excess fluid both intracellularly and extracellularly. Fulminant hepatic failure (FHF) develops cerebral edema by disrupting blood-brain barrier (BBB). However, the mechanisms by which mediator induces brain edema in FHF remain to be elucidated. Here, we assessed a linkage between brain edema and lysophosphatidic acid (LPA) signaling by utilizing an animal model of FHF and in vitro BBB model. Azoxymethane-treated mice developed FHF and hepatic encephalopathy, associated with higher autotaxin (ATX) activities in serum than controls. Using in vitro BBB model, LPA disrupted the structural integrity of tight junction proteins including claudin-5, occludin, and ZO-1. Furthermore, LPA decreased transendothelial electrical resistances in in vitro BBB model, and induced cell contraction in brain endothelial monolayer cultures, both being inhibited by a Rho-associated protein kinase inhibitor, Y-27632. The brain capillary endothelial cells predominantly expressed LPA(6) mRNA, whose knockdown blocked the LPA-induced endothelial cell contraction. Taken together, the up-regulation of serum ATX in hepatic encephalopathy may activate the LPA-LPA(6)-G(12/13)-Rho pathway in brain capillary endothelial cells, leading to enhancement of BBB permeability and brain edema. (C) 2018 Elsevier Inc. All rights reserved.
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