title: Sphingosine 1-phosphate receptor-1 enhances mitochondrial function and reduces cisplatin-induced tubule injury.
abstract: Sphingosine 1-phosphate (S1P), the natural sphingolipid ligand for a family of five G protein- coupled receptors (S1P1-S1P5Rs), regulates cell survival and lymphocyte circulation. We have shown that the pan-S1PR agonist, FTY720, attenuates kidney ischemia-reperfusion injury by directly activating S1P1 on proximal tubule (PT) cells, independent of the canonical lymphopenic effects of S1P1 activation on B and T cells. FTY720 also reduces cisplatin-induced AKI. Therefore, in this study, we used conditional PT-S1P1-null (PepckCreS1pr1(fl/fl)) and control (PepckCreS1pr1(w/wt)) mice to determine whether the protective effect of FTY720 in AKI is mediated by PT-S1P1. Cisplatin induced more renal injury in PT-S1P1-null mice than in controls. Although FTY720 produced lymphopenia in both control and PT-S1P1-null mice, it reduced injury only in control mice. Furthermore, the increase in proinflammatory cytokine (CXCL1, MCP-1, TNF-α, and IL-6) expression and infiltration of neutrophils and macrophages induced by cisplatin treatment was attenuated by FTY720 in control mice but not in PT-S1P1-null mice. Similarly, S1P1 deletion rendered cultured PT cells more susceptible to cisplatin-induced injury, whereas S1P1 overexpression protected PT cells from injury and preserved mitochondrial function. We conclude that S1P1 may have an important role in stabilizing mitochondrial function and that FTY720 administration represents a novel strategy in the prevention of cisplatin-induced AKI.
authors.affiliation: Departments of Medicine and Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia School of Medicine, Charlottesville, Virginia ab9nh@virginia.edu.
authors.forename: Amandeep
authors.initials: A
authors.lastname: Bajwa
authors.affiliation: Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia School of Medicine, Charlottesville, Virginia Pharmacology, and.
authors.forename: Diane L
authors.initials: DL
authors.lastname: Rosin
authors.affiliation: Departments of Medicine and Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia School of Medicine, Charlottesville, Virginia.
authors.forename: Piotr
authors.initials: P
authors.lastname: Chroscicki
authors.affiliation: Departments of Medicine and Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia School of Medicine, Charlottesville, Virginia.
authors.forename: Sangju
authors.initials: S
authors.lastname: Lee
authors.affiliation: Departments of Medicine and Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia School of Medicine, Charlottesville, Virginia.
authors.forename: Krishna
authors.initials: K
authors.lastname: Dondeti
authors.affiliation: Departments of Medicine and Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia School of Medicine, Charlottesville, Virginia.
authors.forename: Hong
authors.initials: H
authors.lastname: Ye
authors.affiliation: Departments of Medicine and Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia School of Medicine, Charlottesville, Virginia.
authors.forename: Gilbert R
authors.initials: GR
authors.lastname: Kinsey
authors.affiliation: Departments of Medicine and Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia School of Medicine, Charlottesville, Virginia.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Stevens
authors.affiliation: Departments of Medicine and Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia School of Medicine, Charlottesville, Virginia.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Jobin
authors.affiliation: Pharmacology, and.
authors.forename: Brandon M
authors.initials: BM
authors.lastname: Kenwood
authors.affiliation: Pharmacology, and.
authors.forename: Kyle L
authors.initials: KL
authors.lastname: Hoehn
authors.affiliation: Pharmacology, and.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Lynch
authors.affiliation: Departments of Medicine and Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia School of Medicine, Charlottesville, Virginia.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Okusa
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019069:Cell Respiration; D002945:Cisplatin; D004353:Drug Evaluation, Preclinical; D004847:Epithelial Cells / Q000187:drug effects; D000068876:Fingolimod Hydrochloride; D007687:Kidney Tubules, Proximal / Q000187:drug effects*; D008297:Male; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects*; D063154:Mitochondrial Dynamics; D011409:Propylene Glycols / Q000494:pharmacology / Q000627:therapeutic use*; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D002945:Cisplatin
keywords: ARF; cisplatin; mitochondria; proximal tubule