Lysophosphatidic acid receptor, LPA6, regulates endothelial blood-brain barrier function: Implication for hepatic encephalopathy.
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.
['Masago|Kayo|K|', 'Kihara|Yasuyuki|Y|', 'Yanagida|Keisuke|K|', 'Hamano|Fumie|F|', 'Nakagawa|Shinsuke|S|', 'Niwa|Masami|M|', 'Shimizu|Takao|T|']
D000818:Animals D001397:Azoxymethane D001812:Blood-Brain Barrier D001929:Brain Edema D002199:Capillary Permeability D002478:Cells, Cultured D042783:Endothelial Cells D006501:Hepatic Encephalopathy D017114:Liver Failure, Acute D008246:Lysophospholipids D008297:Male D008810:Mice, Inbred C57BL D008954:Models, Biological D010727:Phosphoric Diester Hydrolases D051381:Rats D049368:Receptors, Lysophosphatidic Acid D015398:Signal Transduction D020741:rho GTP-Binding Proteins D054460:rho-Associated Kinases
GPCR Lipid mediator Lysophospholipid Neurological diseases ROCK p2ry5