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Sphingosine kinase 2 deficiency increases proliferation and migration of renal mouse mesangial cells and fibroblasts

  • Stephanie Schwalm EMAIL logo , Tankica Maneva Timcheva , Iuliia Filipenko , Mahsa Ebadi , Lotte P. Hofmann , Uwe Zangemeister-Wittke , Josef Pfeilschifter and Andrea Huwiler
Published/Copyright: March 9, 2015
Biological Chemistry
From the journal Biological Chemistry Volume 396 Issue 6-7

Abstract

Both of the sphingosine kinase (SK) subtypes SK-1 and SK-2 catalyze the production of the bioactive lipid molecule sphingosine 1-phosphate (S1P). However, the subtype-specific cellular functions are largely unknown. In this study, we investigated the cellular function of SK-2 in primary mouse renal mesangial cells (mMC) and embryonic fibroblasts (MEF) from wild-type C57BL/6 or SK-2 knockout (SK2ko) mice. We found that SK2ko cells displayed a significantly higher proliferative and migratory activity when compared to wild-type cells, with concomitant increased cellular activities of the classical extracellular signal regulated kinase (ERK) and PI3K/Akt cascades, and of the small G protein RhoA. Furthermore, we detected an upregulation of SK-1 protein and S1P3 receptor mRNA expression in SK-2ko cells. The MEK inhibitor U0126 and the S1P1/3 receptor antagonist VPC23019 blocked the increased migration of SK-2ko cells. Additionally, S1P3ko mesangial cells showed a reduced proliferative behavior and reduced migration rate upon S1P stimulation, suggesting a crucial involvement of the S1P3 receptor. In summary, our data demonstrate that SK-2 exerts suppressive effects on cell growth and migration in renal mesangial cells and fibroblasts, and that therapeutic targeting of SKs for treating proliferative diseases requires subtype-selective inhibitors.

Keywords: fibroblasts; migration; proliferation; renal mesangial cells; sphingosine 1-phosphate; sphingosine kinase
Corresponding author: Stephanie Schwalm, Pharmazentrum Frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany; and Institute of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3010 Bern, Switzerland, e-mail:

Acknowledgments

This work was supported by the Swiss National Science Foundation (3100A0–111806), and the German Research Foundation (SFB1039/TP02). We thank Isolde Römer and Simone Albert for technical assistance.

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Received: 2014-12-1
Accepted: 2015-3-2
Published Online: 2015-3-9
Published in Print: 2015-6-1

©2015 by De Gruyter

Articles in the same Issue

  1. Frontmatter
  2. Guest Editorial
  3. Highlight: Molecular Medicine of Sphingolipids
  4. HIGHLIGHT: MOLECULAR MEDICINE OF SPHINGOLIPIDS
  5. The role of serum amyloid A and sphingosine-1-phosphate on high-density lipoprotein functionality
  6. Sphingolipids in viral infection
  7. Tackling the biophysical properties of sphingolipids to decipher their biological roles
  8. Ceramide and sphingosine in pulmonary infections
  9. Molecular mechanisms of erythrocyte aging
  10. Sphingolipids in liver injury, repair and regeneration
  11. Ultrasound-stimulated microbubble enhancement of radiation response
  12. Innate immune responses in the brain of sphingolipid lysosomal storage diseases
  13. Novel mechanisms of action of classical chemotherapeutic agents on sphingolipid pathways
  14. The role of sphingolipids in endothelial barrier function
  15. The effect of altered sphingolipid acyl chain length on various disease models
  16. Secretory sphingomyelinase in health and disease
  17. Preclinical development of a C6-ceramide NanoLiposome, a novel sphingolipid therapeutic
  18. Sphingomyelin breakdown in T cells: role in activation, effector functions and immunoregulation
  19. The molecular medicine of acid ceramidase
  20. Caenorhabditis elegans as a model to study sphingolipid signaling
  21. S1PR4 is required for plasmacytoid dendritic cell differentiation
  22. Antinociceptive effects of FTY720 during trauma-induced neuropathic pain are mediated by spinal S1P receptors
  23. Subcellular distribution of FTY720 and FTY720-phosphate in immune cells – another aspect of Fingolimod action relevant for therapeutic application
  24. Downregulation of sphingosine 1-phosphate (S1P) receptor 1 by dexamethasone inhibits S1P-induced mesangial cell migration
  25. Sphingosine kinase 2 deficiency increases proliferation and migration of renal mouse mesangial cells and fibroblasts
  26. Obituary
  27. The life and work of Dr. Robert Bittman (1942–2014)
https://doi.org/10.1515/hsz-2014-0289
Keywords for this article
fibroblasts; migration; proliferation; renal mesangial cells; sphingosine 1-phosphate; sphingosine kinase

Articles in the same Issue

  1. Frontmatter
  2. Guest Editorial
  3. Highlight: Molecular Medicine of Sphingolipids
  4. HIGHLIGHT: MOLECULAR MEDICINE OF SPHINGOLIPIDS
  5. The role of serum amyloid A and sphingosine-1-phosphate on high-density lipoprotein functionality
  6. Sphingolipids in viral infection
  7. Tackling the biophysical properties of sphingolipids to decipher their biological roles
  8. Ceramide and sphingosine in pulmonary infections
  9. Molecular mechanisms of erythrocyte aging
  10. Sphingolipids in liver injury, repair and regeneration
  11. Ultrasound-stimulated microbubble enhancement of radiation response
  12. Innate immune responses in the brain of sphingolipid lysosomal storage diseases
  13. Novel mechanisms of action of classical chemotherapeutic agents on sphingolipid pathways
  14. The role of sphingolipids in endothelial barrier function
  15. The effect of altered sphingolipid acyl chain length on various disease models
  16. Secretory sphingomyelinase in health and disease
  17. Preclinical development of a C6-ceramide NanoLiposome, a novel sphingolipid therapeutic
  18. Sphingomyelin breakdown in T cells: role in activation, effector functions and immunoregulation
  19. The molecular medicine of acid ceramidase
  20. Caenorhabditis elegans as a model to study sphingolipid signaling
  21. S1PR4 is required for plasmacytoid dendritic cell differentiation
  22. Antinociceptive effects of FTY720 during trauma-induced neuropathic pain are mediated by spinal S1P receptors
  23. Subcellular distribution of FTY720 and FTY720-phosphate in immune cells – another aspect of Fingolimod action relevant for therapeutic application
  24. Downregulation of sphingosine 1-phosphate (S1P) receptor 1 by dexamethasone inhibits S1P-induced mesangial cell migration
  25. Sphingosine kinase 2 deficiency increases proliferation and migration of renal mouse mesangial cells and fibroblasts
  26. Obituary
  27. The life and work of Dr. Robert Bittman (1942–2014)
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