S1P1-selective agonist, SEW2871, ameliorates ischemic acute renal failure

Lien, Yeong‐Hau H.; Yong, Kim Chong; Cho, C.; Igarashi, Suzu; Lai, Li‐Wen

doi:10.1038/sj.ki.5000360

Cited by 119 publications

(114 citation statements)

References 44 publications

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“…For these reasons, we used SEW2871, a partial S1PR1 receptor agonist that leads to S1PR1 receptor internalization and recycling (23,46). It has been shown to ameliorate ischemia-reperfusion injury in kidneys by decreasing lymphocyte numbers and proinflammatory cytokines, including tumor necrosis factor-a (22). The finding that SEW2871 blocks the development of emphysema after VEGFR inhibition suggests that S1PR1 plays a major role in the maintenance of alveolar septal integrity.…”

Section: Discussionmentioning

confidence: 80%

“…Interestingly, S1PR1 is known to be up-regulated by VEGF (47), suggesting that, although we could not document a decrease in S1PR1 protein expression in response to VEGFR blockade, the inhibited VEGF function may have further weakened the effects of the endogenous S1P on S1PR1 signaling. The finding that S1PR1 agonist was sufficient to inhibit apoptosis and airspace enlargement in this model is encouraging, as this target would theoretically eliminate many of the side effects attributed to the other S1P receptors, such as tachycardia or hypotension (22,23,46).…”

Section: Discussionmentioning

confidence: 85%

“…D-erythro-Sphingosine (20 mg, intraperitoneal; Sigma), or FTY720 (0.1 mg/kg, intraperitoneal; Cayman Chemical, Ann Arbor, MI) (8,14) was given daily for 5 days starting on the day of SU5416 administration, using ethanol (0.1%; intraperitoneal) as vehicle control. SEW2871 (20 mg/kg; Calbiochem) (22,23) was similarly administered by gavage. Mice were harvested 4 weeks after SU5416 administration.…”

Section: Animal Studiesmentioning

confidence: 99%

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Stimulation of Sphingosine 1-Phosphate Signaling as an Alveolar Cell Survival Strategy in Emphysema

Diab¹,

Adamowicz²,

Kamocki³

et al. 2010

Am J Respir Crit Care Med

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Rationale: Vascular endothelial growth factor receptor (VEGFR) inhibition increases ceramides in lung structural cells of the alveolus, initiating apoptosis and alveolar destruction morphologically resembling emphysema. The effects of increased endogenous ceramides could be offset by sphingosine 1-phosphate (S1P), a prosurvival by-product of ceramide metabolism. Objectives: The aims of our work were to investigate the sphingosine-S1P-S1P receptor axis in the VEGFR inhibition model of emphysema and to determine whether stimulation of S1P signaling is sufficient to functionally antagonize alveolar space enlargement. Methods: Concurrent to VEGFR blockade in mice, S1P signaling augmentation was achieved via treatment with the S1P precursor sphingosine, S1P agonist FTY720, or S1P receptor-1 (S1PR1) agonist SEW2871. Outcomes included sphingosine kinase-1 RNA expression and activity, sphingolipid measurements by combined liquid chromatography-tandem mass spectrometry, immunoblotting for prosurvival signaling pathways, caspase-3 activity and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assays, and airspace morphometry. Measurements and Main Results: Consistent with previously reported de novo activation of ceramide synthesis, VEGFR inhibition triggered increases in lung ceramides, dihydroceramides, and dihydrosphingosine, but did not alter sphingosine kinase activity or S1P levels. Administration of sphingosine decreased the ceramide-to-S1P ratio in the lung and inhibited alveolar space enlargement, along with activation of prosurvival signaling pathways and decreased lung parenchyma cell apoptosis. Sphingosine significantly opposed ceramide-induced apoptosis in cultured lung endothelial cells, but not epithelial cells. FTY720 or SEW2871 recapitulated the protective effects of sphingosine on airspace enlargement concomitant with attenuation of VEGFR inhibitor-induced lung apoptosis. Conclusions: Strategies aimed at augmenting the S1P-S1PR1 signaling may be effective in ameliorating the apoptotic mechanisms of emphysema development.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 85%

Section: Animal Studiesmentioning

confidence: 99%

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Stimulation of Sphingosine 1-Phosphate Signaling as an Alveolar Cell Survival Strategy in Emphysema

Diab¹,

Adamowicz²,

Kamocki³

et al. 2010

Am J Respir Crit Care Med

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“…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.…”

Section: Fty720mentioning

confidence: 99%

Sphingosine 1-phosphate chemical biology

Lynch

Macdonald

2008

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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A dozen years ago, the term 'S1P' (sphingosine 1-phosphate) was not in the lexicons of scientific literature databases. By early 2008, this query term retrieved well over 1,000 citations from PubMed -about 225 of these appeared in 2007. Indeed, S1P is arguably the most heavily studied lipid molecule at present. What happened to distinguish S1P among many other signaling lipids? We believe that the seminal event was the linking of the investigational drug, FTY720 (fingolimod), to S1P signaling. This realization profoundly altered understanding of S1P biology, revealing both that S1P is prominent in lymphocyte trafficking and that mimicking S1P signaling with an agonist drug can modulate the immune system to considerable therapeutic benefit. Neither fact was known prior to FTY720; indeed, this molecule is testament to the power of chemical biology. In this communication, we attempt to summarize progress to date in S1P chemical biology. S1P biosynthesis and degradationIn mammals, the long chain base sphingosine is formed by amidase catalyzed hydrolysis of ceramides. Sphingosine is phosphorylated by sphingosine kinase types 1 or 2 (SPHK1, SPHK2) to form S1P, which is either converted back to sphingosine by lipid phosphatases or degraded irreversibly by S1P lyase [1]. S1P synthesis occurs in cells (but see reference [2]), thus the existence of S1P in plasma indicates some efflux system is responsible for S1P's appearance. A small fraction of long chain bases lack a double bond (sphinganine (dihydrosphingosine), which is the precursor to ceramide in mammalian sphingolipid anabolism) [3]. Sphinganine is a substrate of SPHK and the product, sphinganine 1-phosphate, is for the most part indistinguishable from S1P in its biologic effects (but see reference [4]). The S1P biosynthetic pathway is widespread among mammalian tissues. S1P concentrations in human and mouse plasma are 200-800 nanoM, where the molecule is nearly all protein-bound. S1P introduced into the mouse vasculature is degraded quickly (T1/2 15 min [5]), which indicates a rapid flux of sphingosine through the pathway outlined above. Mice lacking either SPHK1 or SPHK2 have decreased plasma S1P concentrations [6][7][8], but the reduction is more pronounced in SPHK1 null animals [6]. Disruption of both Sphk1 and Sphk2 gene loci is embryonic lethal in mice [9]. Characterization of the phosphatase(s) that hydrolyze the S1P phosphate monoester has been problematic. Leading candidates for this enzyme are the integral membrane lipid ectophosphatase LPP3 (lipid © 2008 Elsevier B.V. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers tha...

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“…SEW2871, a S1P(1)-selective agonist, administration improves mouse renal injury induced by ischemia-reperfusion by means of lymphocyte egress suppression and the inhibition of pro-inflammatory factors [168]. FTY720 suppressed hepatocellular carcinoma recurrence after rat liver transplantation in rats [169] and also showed a neuroprotective effect after transient middle cerebral artery occlusion [170].…”

Section: S1p System As a Prospective Remedial Targetmentioning

confidence: 99%