Sphinganine-1-phosphate attenuates both hepatic and renal injury induced by hepatic ischemia and reperfusion in mice.
Hepatic ischemia/reperfusion (I/R) injury is a major complication after liver transplantation, major hepatic resection, or prolonged portal vein occlusion. Furthermore, acute kidney injury is frequent after hepatic I/R and greatly increases postoperative complications. Sphinganine-1-phosphate is a sphingolipid with uncharacterized physiological effects. We serendipitously determined that plasma levels of sphinganine-1-phosphate fell significantly after liver I/R in mice. In this study, we hypothesized that repletion of plasma sphinganine-1-phosphate would protect against liver and kidney injuries after liver I/R. C57BL/6 mice were subjected to 60 min of partial hepatic I/R and treated with either vehicle or with sphinganine-1-phosphate (given immediately before and 2 h after reperfusion). Vehicle-treated mice subjected to liver I/R developed acute liver and kidney injuries with elevated plasma alanine aminotransferase and creatinine 5 and 24 h after liver I/R. However, liver and kidney injuries were significantly attenuated with sphinganine-1-phosphate treatment. Sphinganine-1-phosphate markedly inhibited liver and kidney necrosis and apoptosis 24 h after liver I/R. Moreover, sphinganine-1-phosphate attenuated neutrophil infiltration, reduced plasma IL-6 and TNF-alpha upregulation, and preserved liver and kidney vascular integrity while reducing liver and kidney F-actin degradation after liver I/R. Finally, sphinganine-1-phosphate-mediated hepatic and renal protection was blocked by VPC23019, an antagonist for sphingosine-1-phosphate type 1 receptor. Therefore, sphinganine-1-phosphate improves acute liver and kidney injuries after hepatic I/R via sphingosine-1-phosphate type 1 receptor-mediated inhibition of necrosis and apoptosis and by improving vascular integrity. Harnessing the mechanisms of cytoprotection with sphinganine-1-phosphate activation may lead to new therapies for perioperative hepatic I/R injury and subsequent remote organ injury.
Park
Sang Won
SW
Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York, USA.
Kim
Mihwa
M
Chen
Sean W C
SW
D'Agati
Vivette D
VD
Lee
H Thomas
HT
D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D015850:Interleukin-6 / Q000097:blood; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D008246:Lysophospholipids / Q000097:blood / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000187:drug effects; D049349:Receptors, Lysosphingolipid / Q000819:agonists / Q000097:blood; D015427:Reperfusion Injury / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D000199:Actins; D015850:Interleukin-6; D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; D014409:Tumor Necrosis Factor-alpha; C060506:sphingosine 1-phosphate; D013110:Sphingosine