Activation of Sphingosine-1-Phosphate 1 Receptor in the Proximal Tubule Protects Against Ischemia-Reperfusion Injury

Abstract

Agonists of the sphingosine-1-phosphate receptor (S1PR) attenuate kidney ischemia-reperfusion injury (IRI). Previous studies suggested that S1P 1 R-induced lymphopenia mediates this protective effect, but lymphocyte-independent mechanisms could also contribute. Here, we investigated the effects of S1PR agonists on kidney IRI in mice that lack T and B lymphocytes (Rag-1 knockout mice). Administration of the nonselective S1PR agonist FTY720 or the selective S1P 1 R agonist SEW2871 reduced injury in both Rag-1 knockout and wild-type mice. In vitro, SEW2871 significantly attenuated LPS-or hypoxia/reoxygenation-induced apoptosis in cultured mouse proximal tubule epithelial cells, supporting a direct protective effect of S1P 1 R agonists via mitogen-activated protein kinase and/or Akt pathways. S1P 1 Rs in the proximal tubule mediated IRI in vivo as well: Mice deficient in proximal tubule S1P 1 Rs experienced a greater decline in renal function after IRI than control mice and their kidneys were no longer protected by SEW2871 administration. In summary, S1PRs in the proximal tubule are necessary for stress-induced cell survival, and S1P 1 R agonists are renoprotective via direct effects on the tubule cells. Selective agonists of S1P 1 Rs may hold therapeutic potential for the prevention and treatment of acute kidney injury. 21: 955-965, 201021: 955-965, . doi: 10.1681 Ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI), which is associated with prolonged hospitalization and high morbidity and mortality. The pathogenesis of AKI is complex and involves direct effects on vascular endothelial cells, tubule cells, and immune cells. 1,2 Kidney tubular epithelial cells express both TLR-2 and TLR-4, which are thought to respond to endogenous "danger signals" to initiate AKI. 3 These danger signals activate immune cells, leading to inflammation induced by cytokines, chemokines, and classic innate effector immune cells, such as neutrophils and macrophages. J Am Soc NephrolLymphocytes are important mediators of experimental IRI in the kidney as well as other organs. 4 -6 Lymphocytes contribute to the pathogenesis of IRI, and their absence, such as in mice deficient in B (MT) 7 or T cells (nu/nu) 6,8 or both (Rag-1 knockout [KO]), 6 confers protection from kidney IRI.Sphingosine-1-phosphate (S1P), a sphingolipid that is produced by phosphorylation of sphingosine by sphingosine kinases, is the natural ligand for a

Sphingosine 1-Phosphate Receptor-1 Enhances Mitochondrial Function and Reduces Cisplatin-Induced Tubule Injury

“…Morphologic changes ( Figure 3B) paralleled functional studies (ATN scores: PepckCreS1pr1 wt/wt cisplatin 2.8960.22 versus cisplatin+FTY720 1.6660.21; PepckCreS1pr1 fl/fl cisplatin 3.0860.21 versus cisplatin+FTY720 3.5660.28). As expected, 12,13 FTY720 produced lymphopenia in PepckCreS1pr1 fl/fl and PepckCreS1pr1 wt/wt mice (data not shown). These data demonstrate that PT-S1P1 deficiency enhanced cisplatin-induced injury and that the protective effect of FTY720 in cisplatin-treated mice, as in mice exposed to IRI, 12 is independent of lymphopenia but dependent on expression of S1P1 in PT cells.…”

“…13 The cisplatininduced increase in cleaved-caspase 3 in TKPTS cells was prevented by FTY720-p. S1pr1 deficiency increased basal Figure 3. Deletion of PT S1P1R exacerbates injury and its presence is necessary for FTY720-mediated protection from cisplatin-induced AKI.…”

“…13 To investigate the direct involvement of PT-S1P1 in cisplatin-induced nephrotoxicity, we used conditional deletion of S1pr1 in PT cells 13 (see also tubular epithelial cell [TEC] characterization in Concise Methods). Cisplatin produced significantly more renal injury as measured by plasma creatinine in PepckCreS1pr1 fl/fl than in PepckCreS1pr1 wt/wt (control).…”

“…30 We previously demonstrated that the protective effect of S1P1 agonists FTY720 or SEW2871 in IRI 12 was mediated by activation of S1P1 expressed on PT cells, independent of lymphopenia. 13 Cisplatin use in cancer therapy is often limited by nephrotoxicity, specifically, PT injury. Here, we demonstrated that FTY720, a drug that is approved for use in treating multiple sclerosis, protects kidneys from cisplatin-induced injury.…”

“…We find in vivo that both homozygous knockouts and mice heterozygous for PT S1pr1 deletion are more susceptible to injury, and FTY720 does not provide protection from IRI. 13 Overexpression of S1pr1 rendered TKPTS cells resistant to cisplatin and increased mitochondrial stability, which may contribute to the S1P1-mediated protective mechanism in these cells. These studies, while further emphasizing the protective role of S1P1 in AKI, demonstrate that by directly targeting S1P1 on PTepithelial cells, FTY720 could provide a novel mechanism for protection from cisplatin-induced nephrotoxicity.…”