Selective sphingosine 1-phosphate 1 receptor activation reduces ischemia-reperfusion injury in mouse kidney

Abstract

Selective sphingosine 1-phosphate 1 receptor activation reduces ischemia-reperfusion injury in mouse kidney. Am J Physiol Renal Physiol 290: F1516 -F1524, 2006. First published January 10, 2006 doi:10.1152/ajprenal.00311.2005.-The mechanisms involved in renal ischemia-reperfusion injury (IRI) are complex and appear to involve the early participation of bone marrow-derived cells. T lymphocytes participate in the pathogenesis of IRI. Sphingosine 1-phosphate (S1P) induces peripheral T cell depletion. Therefore, we hypothesized that S1P 1 receptor activation protects kidney from IRI. FTY-720, a non-receptor-selective sphingosine analog, was given intraperitoneally to C57BL/6 mice, and animals were subjected to ischemia for 32 min followed by reperfusion for 24 h. Plasma creatinine, blood count, myeloperoxidase (MPO) activity, and renal histology were determined. IRI led to a marked increase in plasma creatinine, MPO activity, leukocyte infiltration, and vascular permeability. FTY-720 significantly decreased plasma creatinine in a doseresponse manner with a maximal reduction of ϳ73 and ϳ69% with doses of 240 and 48 g/kg, respectively. MPO, leukocyte infiltration, vascular permeability, and peripheral blood lymphocyte counts were markedly decreased with FTY-720 treatment. The protective effect of FTY-720 was reversed with VPC-44116, a selective S1P 1 receptor antagonist. Furthermore, SEW-2871, a selective S1P 1 agonist, significantly decreased plasma creatinine in a dose-response manner with a maximal reduction of ϳ70% with a dose of 10 mg/kg. Analysis of kidneys by light microscopy revealed minimal histological signs of ischemic injury with FTY-720 or SEW-2871 treatment compared with the vehicle group. Using RT-PCR, we found a time-dependent increase in the S1P 1 mRNA expression following IRI that begins after 2 h with the maximum expression at ϳ4 h. We conclude that the protective effect of FTY-720 is due primarily to activation of S1P1 receptors. The mechanism of protection is not known but may be related to peripheral lymphocyte depletion or direct effects on kidney cells expressing S1P1 receptor.FTY-720; inflammation; lymphocyte; acute renal failure NOVEL THERAPEUTIC INTERVENTIONS for preventing or attenuating renal tissue injury following ischemia-reperfusion (IR) remain a focus of significant interest. Although the exact pathogenic mechanisms remain poorly defined, accumulating evidence supports the potential role of inflammation and involvement of the immune system. Previous studies have mainly focused on the participation of neutrophils as mediators of IR injury (IRI) (17, 32); however, recent reports show that lymphocytes contribute to injury (8,40). The observation that injury is ameliorated by depletion of T cells and reconstituted with adoptive transfer of CD4 ϩ cells is evidence that the tissue injury following IR is dependent on CD4 ϩ cells (8), although the mechanism is not fully understood. Renal damage secondary to IRI is frequent in organ transplantation and adversely affects allograft survival. An...

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.…”

“…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. FTY720 reduced the cisplatin-induced increase in the number of macrophages and neutrophils in PepckCreS1pr1 wt/wt kidneys but was ineffective in PepckCreS1pr1 fl/fl mice (Supplemental Figure 2).…”

“…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.…”

“…The histologic change in the outer medulla was expressed as ATN, scored on a scale of 1-5, as previously described. 12 Quantitative Real-Time RT-PCR Total RNA was extracted, and single-stranded cDNA was synthesized as previously described. 12,13 Primers were obtained from Integrated DNA Technologies (Coralville, IA); primer sequences for S1P1-5, 12 CXCL1, IL-6, and TNF-a, 28 and IL-1b and MCP-1 48 were as described previously.…”

Sphingosine 1-phosphate chemical biology

“…In addition to the disease models mentioned above, FTY720 has been documented to be efficacious in models of neoplastic disease [40], atherosclerosis [41], renal ischemia reperfusion injury [42][43][44], pain [45], angiogenesis [46], acute lung injury [47], and others. It is worth noting that FTY720 might have actions independent of its phosphorylation to FTY720-P.…”