title: Sphinganine-1-phosphate protects kidney and liver after hepatic ischemia and reperfusion in mice through S1P1 receptor activation.
abstract: 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.
authors.affiliation: Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, NY 10032-3784, USA.
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Park
authors.forename: Mihwa
authors.initials: M
authors.lastname: Kim
authors.forename: Sean W C
authors.initials: SW
authors.lastname: Chen
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Brown
authors.forename: Vivette D
authors.initials: VD
authors.lastname: D'Agati
authors.forename: H Thomas
authors.initials: HT
authors.lastname: Lee
mesh_terms: D058186:Acute Kidney Injury; D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000494:pharmacology; D007511:Ischemia; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008107:Liver Diseases / Q000517:prevention & control*; D008246:Lysophospholipids; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000494:pharmacology; D010069:Oxadiazoles; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015427:Reperfusion Injury / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D013876:Thiophenes
chemical_list: D008246:Lysophospholipids; D010069:Oxadiazoles; D049349:Receptors, Lysosphingolipid; C503964:SEW2871; D013876:Thiophenes; C060504:dihydrosphingosine 1-phosphate; C060506:sphingosine 1-phosphate; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D013110:Sphingosine
references.citation: J Cell Sci. 2005 Oct 15;118(Pt 20):4605-12
references.pmid: 16219683
references.citation: Exp Mol Pathol. 2003 Apr;74(2):86-93
references.pmid: 12710939
references.citation: Kidney Int. 2006 May;69(9):1601-8
references.pmid: 16572108
references.citation: Cardiovasc Res. 2009 May 1;82(2):212-20
references.pmid: 19233865
references.citation: Br J Pharmacol. 2004 Jul;142(5):851-60
references.pmid: 15197107
references.citation: Am J Surg. 2001 Feb;181(2):160-6
references.pmid: 11425059
references.citation: FASEB J. 1999 Nov;13(14):2061-70
references.pmid: 10544189
references.citation: Nat Cell Biol. 2000 Sep;2(9):645-52
references.pmid: 10980706
references.citation: Thromb Haemost. 2008 Jul;100(1):119-26
references.pmid: 18612546
references.citation: Kidney Int. 2007 Jun;71(12):1223-31
references.pmid: 17377506
references.citation: IUBMB Life. 2001 Dec;52(6):303-7
references.pmid: 11895079
references.citation: Scand J Clin Lab Invest. 1965;17(4):381-7
references.pmid: 5838275
references.citation: Cancer Res. 1996 Jan 15;56(2):273-9
references.pmid: 8542580
references.citation: Biochem Soc Symp. 1999;64:79-89
references.pmid: 10207622
references.citation: Am J Transplant. 2005 Jan;5(1):40-9
references.pmid: 15636610
references.citation: J Biol Chem. 2004 Apr 2;279(14):13839-48
references.pmid: 14732717
references.citation: Am J Transplant. 2002 Oct;2(9):843-9
references.pmid: 12392290
references.citation: Biochem J. 2006 Aug 1;397(3):461-71
references.pmid: 16623665
references.citation: Biochem Biophys Res Commun. 2006 Jul 21;346(1):293-300
references.pmid: 16756949
references.citation: Am J Physiol Renal Physiol. 2006 Jun;290(6):F1516-24
references.pmid: 16403835
references.citation: J Cell Biochem. 2004 Aug 1;92(5):882-99
references.pmid: 15258913
references.citation: J Am Soc Nephrol. 2004 Jan;15(1):102-11
references.pmid: 14694162
references.citation: Nat Chem Biol. 2006 Aug;2(8):434-41
references.pmid: 16829954
references.citation: Kidney Int. 2008 Jun;73(11):1220-30
references.pmid: 18322542
references.citation: Exp Cell Res. 2000 Apr 10;256(1):34-41
references.pmid: 10739649
references.citation: Br J Pharmacol. 2005 Oct;146(3):445-55
references.pmid: 16086037
references.citation: Cell Signal. 2006 Oct;18(10):1779-92
references.pmid: 16529909
references.citation: Methods. 2005 Feb;35(2):126-38
references.pmid: 15649839
references.citation: J Am Soc Nephrol. 2001 Feb;12(2):233-240
references.pmid: 11158213
references.citation: Mol Cell Biol. 1999 Aug;19(8):5800-10
references.pmid: 10409766
references.citation: Am J Physiol Renal Physiol. 2002 May;282(5):F844-52
references.pmid: 11934694
references.citation: J Med Chem. 2002 Oct 10;45(21):4629-38
references.pmid: 12361389
references.citation: Transplantation. 1993 Jun;55(6):1265-72
references.pmid: 7685932
references.citation: Exp Nephrol. 2002;10(5-6):383-92
references.pmid: 12381923
references.citation: Cell Stress Chaperones. 2001 Jan;6(1):49-58
references.pmid: 11525243
references.citation: Hum Mol Genet. 2002 May 1;11(9):1137-51
references.pmid: 11978772
references.citation: Kidney Int. 2009 Apr;75(8):809-23
references.pmid: 19190680
references.citation: Shock. 2010 Jan;33(1):31-42
references.pmid: 19752779
references.citation: Prog Nucleic Acid Res Mol Biol. 2002;71:493-511
references.pmid: 12102559
references.citation: Mol Cell Biol. 2002 Feb;22(3):816-34
references.pmid: 11784858
references.citation: Basic Res Cardiol. 2001 Apr;96(2):136-42
references.pmid: 11327331
references.citation: J Appl Physiol (1985). 2003 Mar;94(3):1193-203
references.pmid: 12482769
references.citation: J Biol Chem. 2004 Jul 9;279(28):29367-73
references.pmid: 15138255
references.citation: J Am Soc Nephrol. 2006 Nov;17(11):3115-23
references.pmid: 16988058
references.citation: J Biol Chem. 1999 Feb 19;274(8):4626-32
references.pmid: 9988698
references.citation: Am J Physiol. 1999 Jul;277(1):L159-66
references.pmid: 10409243
references.citation: Biochim Biophys Acta. 2006 Dec;1758(12):2016-26
references.pmid: 16996023
references.citation: Am J Physiol Heart Circ Physiol. 2005 Feb;288(2):H971-6
references.pmid: 15358610
references.citation: Cardiovasc Res. 2004 Aug 1;63(2):305-12
references.pmid: 15249188
references.citation: Psychopharmacology (Berl). 2003 Apr;166(4):366-72
references.pmid: 12589527
references.citation: Lab Invest. 2009 Feb;89(2):196-208
references.pmid: 19079326
references.citation: Liver Transpl. 2002 Feb;8(2):91-109
references.pmid: 11862584
references.citation: Am J Physiol Renal Physiol. 2007 Dec;293(6):F1847-57
references.pmid: 17928414