Sphingosine kinase 1 and 2 regulate the capacity of mesangial cells to resist apoptotic stimuli in an opposing manner

Hofmann, Lotte P.; Ren, Shen; Schwalm, Stephanie; Pfeilschifter, Josef; Huwiler, Andrea

doi:10.1515/bc.2008.160

Cited by 53 publications

(40 citation statements)

References 42 publications

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“…In this context, Hofmann et al [13] investigated the role of the two SK isoforms, SK-1 and SK-2, in staurosporine induced apoptosis. They showed that renal MCs isolated from SK-2 knockout mice were resistant to staurosporine-induced apoptosis whereas the absence of SK-1 led to a more pronounced apoptotic response to staurosporine.…”

Section: S1p In Renal Cellsmentioning

confidence: 99%

“…Because of its highly bioactive properties S1P is an attractive target for the treatment of several diseases. Since the expression of SKs as well as S1PRs was demonstrated in kidney lysates as well as in isolated renal cells [8,9,10,11,12,13], questions about the physiological and pathophysiological functions of S1P in this organ have been raised. Here, we summarize the current state of knowledge about S1P-mediated functions in the kidney.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: S1p In Renal Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sphingosine 1-Phosphate in Renal Diseases

Koch

Pfeilschifter

Huwiler

2013

Cell Physiol Biochem

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“…An unusual pathway in mammalian cells for the salvage of sphingosine back into ceramide has been uncovered that requires its phosphorylation by SphK2 (but not SphK1) and then dephosphorylation by SPP1 (but not SPP2) before it can be reacylated to ceramide by CerS (11). Similarly, renal mesangial cells isolated from SphK2-, but not SphK1-knockout mice, had increased levels of sphingosine (12). This seemingly futile cycle has previously been demonstrated to occur in yeast (13), suggesting that this is an evolutionarily conserved pathway.…”

Section: Opposing Roles Of Sphk1 and Sphk2 In Sphingolipid Metabolism?mentioning

confidence: 99%

Sphingosine-1-phosphate: the Swiss army knife of sphingolipid signaling

Maceyka

Milstien

Spiegel

2009

Journal of Lipid Research

113

103

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The sphingolipid metabolite sphingosine-1-phosphate (S1P) and the kinases that produce it have emerged as critical regulators of numerous fundamental biological processes important for health and disease. Activation of sphingosine kinases (SphKs) by a variety of agonists increases intracellular S1P, which in turn can be secreted out of the cell and bind to and signal through S1P receptors (S1PRs) in an autocrine and/or paracrine manner. Recent studies suggest that this "inside-out" signaling by S1P may play a role in many human diseases. As the roles of the S1PRs in cell and organismal physiology are discussed elsewhere in this volume, we focus this review mainly on recent reports showing how SphKs are activated and S1P reaches its receptors, the role of SphKs and S1P in regulating sphingolipid homeostasis, and the potential importance of the SphK/S1P axis as a therapeutic target in human diseases. Sphingolipids are ubiquitous components of all membranes in eukaryotic cells. Analogous to the lipid signaling molecules derived from metabolism of glycerolipids, sphingolipids produce bioactive sphingolipid metabolites such as sphingosine, sphingosine-1-phosphate (S1P), ceramide, and ceramide-1-phosphate that have key roles in regulating many important physiological and pathological functions (1). Signal-induced activation of several types of sphingomyelinases generates ceramide in a variety of compartments within the cell. Deacylation of ceramide by ceramidases yields sphingosine, the most common sphingoid base in mammals. Sphingoid bases can be recycled into complex sphingolipids or phosphorylated by one of two sphingosine kinase isozymes (SphK1 and SphK2) to form S1P. There are two pathways of S1P degradation: reversible dephosphorylation to sphingosine by nonspecific phosphatases, including lysosomal and lipid-specific phosphatases, and by two S1P-specific phosphatases, SPP1 and SPP2; and irreversible cleavage by S1P lyase (SPL), which can lead to the formation of phosphatidylethanolamine. The latter is the only pathway for degradation of sphingoid bases in mammalian cells.Ceramide, sphingosine, and S1P are readily interconvertable, which is of great significance not only because they are potent signaling molecules, but they also regulate cell growth and survival in different manners. Ceramide and sphingosine are important regulatory components of stress responses, typically inducing growth arrest and apoptosis (1). Conversely, S1P inhibits apoptosis and promotes proliferation (2). Thus, the dynamic balance between S1P and its precursors, ceramide and sphingosine, and their consequent regulation of opposing signaling pathways is an important factor that determines cell fate (3). Although many of the effects of S1P result from its action as a ligand for a family of five G protein-coupled receptors, denoted S1P 1-5 , there is some evidence indicating that S1P can also act through still not yet well-characterized intracellular targets (2). COULD S1P BE A CENTRAL REGULATOR OF SPHINGOLIPID METABOLISM?Many stu...

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“…22,[35][36][37] Mice overexpressing the human Sphk2 gene were generated by GenOway (Lyon Cedex, France). Briefly, human Sphk2 transgene controlled by the ubiquitous CAG promoter was introduced into the Hprt locus by homologous recombination.…”

Section: Animal Proceduresmentioning

confidence: 99%

Sphingosine Kinase 2 Modulates Retinal Neovascularization in the Mouse Model of Oxygen-Induced Retinopathy

Eresch

Stumpf

Koch

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Neovascularization is a major cause of blindness in various ocular diseases. Bioactive sphingosine 1-phosphate (S1P), synthesized by two sphingosine kinases (Sphk1, Sphk2), emerged as a key player in a multitude of cellular processes, including cell survival, proliferation, inflammation, migration, and angiogenesis. We investigated the role of Sphk2, S1P, and S1P receptors (S1PR) during retinal neovascularization using the oxygen-induced retinopathy mouse model (OIR). METHODS. Sphk2 overexpressing (tgSphk2) and Sphk2 knockout (Sphk2) mice were used in the OIR model, exposed to 75% O 2 over 5 days from postnatal day (P)7 to 12 to initiate vessel regression. After returning to room air, these mice developed a marked neovascularization. Retinae recovered from untreated and treated eyes at P7, P12, P14, and P17 were used for lectin-stained retinal whole mounts, mass spectrometry, and quantitative real-time PCR.RESULTS. tgSphk2 mice showed higher retinal S1P concentrations, accelerated retinal angiogenesis, and increased neovascularization. Expression of S1PR, vascular endothelial growth factor a (VEGFa), and angiopoietin 1 and 2 was differentially regulated during the course of OIR in the different genotypes. Sphk2À/À displayed a markedly reduced retinal angiogenesis and neovascularization as well as decreased VEGFa and angiopoietin expression.CONCLUSIONS. Using genetic models of Sphk2 overexpression or deletion we demonstrate a strong impact of Sphk2/S1P on retinal vasculopathy and expression of vascular growth factors like VEGF and angiopoietin in the retina. Consequently, Sphk2, S1P, and S1PR may offer attractive novel therapeutic targets for ischemic retinopathies.

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Sphingosine kinase 1 and 2 regulate the capacity of mesangial cells to resist apoptotic stimuli in an opposing manner

Cited by 53 publications

References 42 publications

Sphingosine 1-Phosphate in Renal Diseases

Sphingosine 1-Phosphate in Renal Diseases

Sphingosine-1-phosphate: the Swiss army knife of sphingolipid signaling

Sphingosine Kinase 2 Modulates Retinal Neovascularization in the Mouse Model of Oxygen-Induced Retinopathy

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