Format

Send to

Choose Destination
Biochem Biophys Res Commun. 2018 Jul 2;501(4):1048-1054. doi: 10.1016/j.bbrc.2018.05.106. Epub 2018 May 24.

Lysophosphatidic acid receptor, LPA6, regulates endothelial blood-brain barrier function: Implication for hepatic encephalopathy.

Author information

1
Department of Biochemistry and Molecular Biology, Department of Lipidomics, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
2
Department of Biochemistry and Molecular Biology, Department of Lipidomics, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address: kihara-yasuyuki@umin.net.
3
Department of Biochemistry and Molecular Biology, Department of Lipidomics, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Department of Lipid Signaling, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan; Vascular Biology Program, Boston Children's Hospital, Boston, MA 20115, USA; Department of Surgery, Harvard Medical School, Boston, MA 20115, USA.
4
Department of Biochemistry and Molecular Biology, Department of Lipidomics, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Department of Lipid Signaling, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
5
Department of Pharmacology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523, Japan.
6
Department of Pharmacology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523, Japan; PharmaCo-Cell Company Ltd., Nagasaki 852-0862, Japan.

Abstract

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 LPA6 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-LPA6-G12/13-Rho pathway in brain capillary endothelial cells, leading to enhancement of BBB permeability and brain edema.

KEYWORDS:

GPCR; Lipid mediator; Lysophospholipid; Neurological diseases; ROCK; p2ry5

PMID:
29778535
PMCID:
PMC6108890
[Available on 2019-07-02]
DOI:
10.1016/j.bbrc.2018.05.106
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center