title: Selective deletion of the endothelial sphingosine-1-phosphate 1 receptor exacerbates kidney ischemia-reperfusion injury.
abstract: The role for the endothelial sphingosine-1-phosphate 1 receptor (S1P1R) in acute kidney injury (AKI) remains unclear as germline endothelial S1P1R deletion is embryonically lethal. Here, we generated conditional endothelial S1P1R deficiency by crossing mice with floxed S1P1R with mice expressing a tamoxifen-inducible form of Cre recombinase under the transcriptional control of the platelet-derived growth factor-β (Pdgfβ) gene. Mice with tamoxifen-induced deletion of endothelial S1P1R had increased renal tubular necrosis, inflammation, and impaired vascular permeability, as well as exacerbated renal tubular apoptosis after ischemic AKI compared with tamoxifen-treated wild-type mice. Moreover, endothelial S1P1R deletion resulted in increased hepatic injury after ischemic AKI. As a potential mechanism for exacerbated renal injury, conditional endothelial S1P1R-null mice had markedly reduced endothelial HSP27 expression compared with wild-type mice. Cultured glomerular endothelial cells treated with a specific S1P1R antagonist (W146) for 3 days also showed reduced HSP27 expression compared with vehicle-treated cells. Finally, mice treated with W146 for 3 days also showed reduced endothelial HSP27 expression as well as exacerbated renal and hepatic injury after ischemic AKI. Thus, our studies demonstrate a protective role for endothelial S1P1R against ischemic AKI most likely by regulating endothelial barrier integrity and endothelial HSP27 expression.
authors.affiliation: Department of Anesthesiology, Anesthesiology Research Laboratories, College of Physicians and Surgeons of Columbia University, Columbia University, New York, New York, USA.
authors.forename: Ahrom
authors.initials: A
authors.lastname: Ham
authors.affiliation: Department of Anesthesiology, Anesthesiology Research Laboratories, College of Physicians and Surgeons of Columbia University, Columbia University, New York, New York, USA.
authors.forename: Mihwa
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Anesthesiology, Anesthesiology Research Laboratories, College of Physicians and Surgeons of Columbia University, Columbia University, New York, New York, USA.
authors.forename: Joo Yun
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Anesthesiology, Anesthesiology Research Laboratories, College of Physicians and Surgeons of Columbia University, Columbia University, New York, New York, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Brown
authors.affiliation: UCL Institute of Ophthalmology, University College London, London, UK.
authors.forename: Marcus
authors.initials: M
authors.lastname: Fruttiger
authors.affiliation: Department of Pathology, College of Physicians and Surgeons of Columbia University, New York, New York, USA.
authors.forename: Vivette D
authors.initials: VD
authors.lastname: D'Agati
authors.affiliation: Department of Anesthesiology, Anesthesiology Research Laboratories, College of Physicians and Surgeons of Columbia University, Columbia University, New York, New York, USA.
authors.forename: H Thomas
authors.initials: HT
authors.lastname: Lee
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002199:Capillary Permeability; D042783:Endothelial Cells / Q000378:metabolism; D004727:Endothelium / Q000378:metabolism*; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000473:pathology; D008107:Liver Diseases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009336:Necrosis; D020556:Neutrophil Infiltration; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism*
chemical_list: D055551:HSP27 Heat-Shock Proteins; C486699:Hspb2 protein, mouse; D049349:Receptors, Lysosphingolipid
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