FTY 720 prevents ischemic reperfusion damage in rat kidneys

Troncoso, P.; Ortiz, Mauricio; Martinez, L.; Kahan, Barry D.

doi:10.1016/s0041-1345(00)02349-6

Cited by 40 publications

(30 citation statements)

References 10 publications

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“…Furthermore, the protective effect of FTY-720 is mimicked by a selective S1P 1 agonist, SEW-2871. Although previous studies have demonstrated that FTY-720 is protective following kidney IRI (38), our studies extend these preliminary observations and provide data on the optimal dose of FTY-720 that confers renal tissue protection and evidence that the specific activation of S1P 1 receptors expressed on leukocytes and/or kidney tissue mediates tissue protection.…”

Section: Discussionsupporting

confidence: 75%

“…The possible mechanism of its immunomodulation was related to sequestration of peripheral blood lymphocytes to secondary lymphoid organs and selective induction of infiltrated lymphocyte apoptosis (23,31,39). Recently, FTY-720 has been found to be able to prevent IRI in the liver (1,22) and kidneys (38); however, these studies mainly focused on FTY-720-induced lymphope- nia. Our study extends these findings and demonstrates that specific S1P 1 receptor activation by FTY-720 induces tissue protection.…”

Section: Discussionmentioning

confidence: 99%

“…In tissues subjected to IRI, lymphocytes are known to contribute to early injury (8,41). In this setting, FTY-720 has also been demonstrated to reduce IRI in kidney (38) and liver (1,22). In vivo, FTY-720 is phosphorylated (FTY-720-P) by sphingosine kinase to form a potent sphingosine 1-phosphate (S1P) analog.…”

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confidence: 99%

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

Awad

Huang

et al. 2006

American Journal of Physiology-Renal Physiology

209

213

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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...

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

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

Awad

Huang

et al. 2006

American Journal of Physiology-Renal Physiology

209

213

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“…This hypothesis was further strengthened by various studies using the immunomodulatory agent FTY720. Thus, Troncoso et al [81] demonstrated that FTY720 prevented ischemic reperfusion damage in a rat kidney model. Since FTY720 in its active phosphorylated form is an unselective S1PR agonist, acting on S1P 1 and S1P 3-5 , the question came up which receptor subtype would mediate this protective effect of FTY720.…”

Section: S1p In Renal Disease Modelsmentioning

confidence: 99%

Sphingosine 1-Phosphate in Renal Diseases

Koch

Pfeilschifter

Huwiler

2013

Cell Physiol Biochem

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Because of its highly bioactive properties sphingosine 1-phosphate (S1P) is an attractive target for the treatment of several diseases. Since the expression of sphingosine kinases as well as S1P receptors was demonstrated in the kidney, questions about the physiological and pathophysiological functions of S1P in this organ have been raised. In this review, we summarize the current state of knowledge about S1P-mediated functions in the kidney. A special focus is put on S1P modulated signal transduction in renal glomerular and tubular cells and consequences for the development and treatment of several kidney diseases, diabetic nephropathy, glomerulonephritis, ischemia-reperfusion injury, as well as for Wilms tumor progression.

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“…FTY720 is being tested in human trials for the indications renal transplantation and multiple sclerosis (5). Further, there is mounting evidence that S1P agonists are efficacious in animal models of atherosclerosis (6), renal ischemia-reperfusion injury (7), and acute lung injury (8).…”

mentioning

confidence: 99%

Sphingosine Kinase 2 Is Required for Modulation of Lymphocyte Traffic by FTY720

Kharel

Lee

Snyder

et al. 2005

Journal of Biological Chemistry

199

180

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Immunotherapeutic drugs that mimic sphingosine 1-phosphate (S1P) disrupt lymphocyte trafficking and cause T helper and T effector cells to be retained in secondary lymphoid tissue and away from sites of inflammation. The prototypical therapeutic agent, 2-alkyl-2-amino-1,3-propanediol (FTY720), stimulates S1P signaling pathways only after it is phosphorylated by one or more unknown kinases. We generated sphingosine kinase 2 (SPHK2) null mice to demonstrate that this kinase is responsible for FTY720 phosphorylation and thereby its subsequent actions on the immune system. Both systemic and lymphocyte-localized sources of SPHK2 contributed to FTY720 induced lymphopenia. Although FTY720 was selectively activated in vivo by SPHK2, other S1P pro-drugs can be phosphorylated to cause lymphopenia through the action of additional sphingosine kinases. Our results emphasize the importance of SPHK2 expression in both lymphocytes and other tissues for immune modulation and drug metabolism.Sphingosine 1-phosphate (S1P) 2 receptor agonists are likely to be the next generation of pharmacologic agents used to modulate immune system function. The prototype drug of this class is FTY720, which is highly efficacious in prolonging allograft survival and in ameliorating autoimmune disease in a variety of animal models (1-4). FTY720 is being tested in human trials for the indications renal transplantation and multiple sclerosis (5). Further, there is mounting evidence that S1P agonists are efficacious in animal models of atherosclerosis (6), renal ischemia-reperfusion injury (7), and acute lung injury (8).FTY720 is a sphingosine analog that, after activation by phosphorylation (to FTY720-P), disrupts lymphocyte trafficking by decreasing lymphocyte egress from lymph nodes and the thymus (9, 10). Although the precise mechanisms that underlie this phenomenon are uncertain, the profound lymphopenia that is the index of FTY720 action is dependent on agonist action at lymphocyte S1P 1 receptors. Since FTY720-P is also a potent agonist at the S1P 3 , S1P 4 , and S1P 5 receptors (11, 12), it remains unknown whether the multiple therapeutic benefits of the drug correlate with agonist activity at the S1P 1 receptor. The propensity for S1P 1 receptor responses to desensitize (13) and the similar behaviors of S1P 1 receptor null thymocytes and FTY720-treated mouse lymphocytes have led to the suggestion that FTY720-P is a functional antagonist (14). In this scenario, the drug exaggerates S1P tone to the extent that the lymphocyte S1P 1 receptor signaling is chronically down-regulated.The kinase(s) responsible for FTY720 activation is the gateway whereby S1P signaling can be accessed readily with a therapeutic agent. Knowledge of this enzyme is important specifically to guide S1P prodrug design and generally to gain insight into the normal role of S1P in immune function. The identity of the kinase is not known currently; two candidates are sphingosine kinase 1 (SPHK1) and sphingosine kinase 2 (SPHK2). These enzymes, which are expressed widely, catalyz...

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FTY 720 prevents ischemic reperfusion damage in rat kidneys

Cited by 40 publications

References 10 publications

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

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

Sphingosine 1-Phosphate in Renal Diseases

Sphingosine Kinase 2 Is Required for Modulation of Lymphocyte Traffic by FTY720

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