Lysophosphatidic acid receptor, LPA6, regulates endothelial blood-brain barrier function: Implication for hepatic encephalopathy
- Department of Biochemistry and Molecular Biology, Department of Lipidomics, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033 (Japan)
- Department of Pharmacology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523 (Japan)
Highlights: • Serum autotaxin activity is elevated in the mouse with brain edema. • LPA{sub 6} is predominantly expressed in rat brain capillary endothelial cells. • LPA–LPA{sub 6}–G{sub 12/13}–Rho pathway regulates blood brain barrier permeability. 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{sub 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{sub 6}–G{sub 12/13}–Rho pathway in brain capillary endothelial cells, leading to enhancement of BBB permeability and brain edema.
- OSTI ID:
- 23125050
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 501, Issue 4; Other Information: Copyright (c) 2018 Elsevier Inc. All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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