title: Sphingosine kinase 1 protects against renal ischemia-reperfusion injury in mice by sphingosine-1-phosphate1 receptor activation.
abstract: The roles of sphingosine kinases SK1 and SK2 in ischemia-reperfusion injury have not been fully elucidated since studies have found beneficial effects of SK1 while others showed no role in this injury. To help resolve this, we used SK1 or SK2 knockout mice and confirmed that renal ischemia-reperfusion injury induced SK1, but not SK2, in the kidneys. Furthermore, knockout or pharmacological inhibition of SK1 increased injury after renal ischemia-reperfusion injury. In contrast, lack of SK2 conferred renal protection following injury. In addition, we used lentiviral gene delivery to selectively express enhanced green fluorescent protein (EGFP) or human SK1 coexpressed with EGFP (EGFP-huSK1) in the kidney. Mice with kidney-specific overexpression of EGFP-huSK1 had significantly improved renal function with lower plasma creatinine, renal necrosis, apoptosis, and inflammation. Moreover, EGFP-huSK1 overexpression in cultured human proximal tubule (HK-2) cells protected against peroxide-induced necrosis. Selective overexpression of EGFP-huSK1 led to increased HSP27 mRNA and protein expression in vivo and in vitro. Functional protection as well as induction of HSP27 with EGFP-huSK1 overexpression in vivo was blocked with sphingosine-1-phosphate-1 receptor(1) (S1P(1)) antagonism. Thus, our findings suggest that SK1 is renoprotective by S1P(1) activation and perhaps HSP27 induction. Kidney-specific expression of SK1 through lentiviral delivery may be a viable therapeutic option to attenuate renal ischemia-reperfusion injury.
authors.affiliation: Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York, USA.
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Park
authors.forename: Minjae
authors.initials: M
authors.lastname: Kim
authors.forename: Mihwa
authors.initials: M
authors.lastname: Kim
authors.forename: Vivette D
authors.initials: VD
authors.lastname: D'Agati
authors.forename: H Thomas
authors.initials: HT
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000097:blood; D002460:Cell Line; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D016086:Lentivirus / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018832:Molecular Chaperones; D009336:Necrosis; D020556:Neutrophil Infiltration; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D000081025:Sphingosine-1-Phosphate Receptors; D013997:Time Factors; D000099157:Sphingosine Kinase
chemical_list: D015415:Biomarkers; D003404:Creatinine; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D018836:Inflammation Mediators; D018832:Molecular Chaperones; D017853:Phosphotransferases (Alcohol Group Acceptor); D047428:Protein Kinase Inhibitors; D049349:Receptors, Lysosphingolipid; D011993:Recombinant Fusion Proteins; D000081025:Sphingosine-1-Phosphate Receptors; D000099157:Sphingosine Kinase; C057725:HSPB1 protein, human; C486699:Hspb2 protein, mouse; C477362:S1PR1 protein, human; C556330:S1pr1 protein, mouse