sew2871 and Liver-Diseases

Functional and structural damages in sinusoidal endothelial cells (SECs) have a crucial role during hepatic ischemia-reperfusion injury (IRI). In regulating endothelial function, sphingosine-1-phosphate receptor 1 (S1PR1), which is a G protein-coupled receptor, has an important role. The present study aimed to clarify whether SEW2871, a selective S1PR1 agonist, can attenuate hepatic damage caused by hepatic IRI, focusing on SEC functions.. In vivo, using a 60-min partial-warm IRI model, mice were treated with SEW2871 or without it (with vehicle). In vitro, isolated SECs pretreated with SEW2871 or without it (with vehicle) were incubated with hydrogen peroxide.. Compared with the IRI + vehicle group, SEW2871 administration significantly improved serum transaminase levels and liver damage, attenuated infiltration of Ly-6G and mouse macrophage antigen-1-positive cells, suppressed the expression of vascular cell adhesion molecule-1 and proinflammatory cytokines in the liver, and enhanced the expressions of endothelial nitric oxide synthase (eNOS) and vascular endothelial (VE) cadherin in the liver (eNOS/β-actin [median]: 0.24 versus 0.53, P = 0.008; VE-cadherin/β-actin [median]: 0.21 versus 0.94, P = 0.008). In vitro, compared with the vehicle group, pretreatment of SECs with SEW2871 significantly increased the expressions of eNOS and VE-cadherin (eNOS/β-actin [median]: 0.22 versus 0.29, P = 0.008; VE-cadherin/β-actin [median]: 0.38 versus 0.67, P = 0.008). As results of investigation of prosurvival signals, SEW2871 significantly increased Akt phosphorylation in SECs and decreased lactate dehydrogenase levels in supernatants of SECs.. These results indicate that S1PR1 agonist induces attenuation of hepatic IRI, which might be provided by preventing SEC damage. S1PR1 may be a therapeutic target for the prevention of early sinusoidal injury after hepatic IRI.

Topics: Animals; Antigens, CD; Cadherins; Cytokines; Drug Evaluation, Preclinical; Endothelial Cells; Liver; Liver Diseases; Male; Mice; Mice, Inbred C57BL; Nitric Oxide Synthase Type III; Oxadiazoles; Proto-Oncogene Proteins c-akt; Random Allocation; Receptors, Lysosphingolipid; Reperfusion Injury; Sphingosine-1-Phosphate Receptors; Thiophenes; Vascular Cell Adhesion Molecule-1

Liver failure due to ischemia and reperfusion (IR) and subsequent acute kidney injury are significant clinical problems. We showed previously that liver IR selectively reduced plasma sphinganine-1-phosphate levels without affecting sphingosine-1-phosphate (S1P) levels. Furthermore, exogenous sphinganine-1-phosphate protected against both liver and kidney injury induced by liver IR. In this study, we elucidated the signaling mechanisms of sphinganine-1-phosphate-mediated renal and hepatic protection. A selective S1P(1) receptor antagonist blocked the hepatic and renal protective effects of sphinganine-1-phosphate, whereas a selective S1P(2) or S1P(3) receptor antagonist was without effect. Moreover, a selective S1P(1) receptor agonist, SEW-2871, provided similar degree of liver and kidney protection compared with sphinganine-1-phosphate. Furthermore, in vivo gene knockdown of S1P(1) receptors with small interfering RNA abolished the hepatic and renal protective effects of sphinganine-1-phosphate. In contrast to sphinganine-1-phosphate, S1P's hepatic protection was enhanced with an S1P(3) receptor antagonist. Inhibition of extracellular signal-regulated kinase, Akt or pertussis toxin-sensitive G-proteins blocked sphinganine-1-phosphate-mediated liver and kidney protection in vivo. Taken together, our results show that sphinganine-1-phosphate provided renal and hepatic protection after liver IR injury in mice through selective activation of S1P(1) receptors and pertussis toxin-sensitive G-proteins with subsequent activation of ERK and Akt.

Topics: Acute Kidney Injury; Animals; Extracellular Signal-Regulated MAP Kinases; Ischemia; Kidney; Liver; Liver Diseases; Lysophospholipids; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Oxadiazoles; Proto-Oncogene Proteins c-akt; Receptors, Lysosphingolipid; Reperfusion Injury; Signal Transduction; Sphingosine; Thiophenes