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

Schwalm, Stephanie; Maneva Timcheva, Tankica; Filipenko, Iuliia; Ebadi, Mahsa; Hofmann, Lotte P; Zangemeister-Wittke, Uwe; Pfeilschifter, Josef; Huwiler, Andrea (2015). Sphingosine kinase 2 deficiency increases proliferation and migration of renal mouse mesangial cells and fibroblasts. Biological chemistry, 396(6-7), pp. 813-825. De Gruyter 10.1515/hsz-2014-0289

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Schwalm, Stephanie; Maneva Timcheva, Tankica; Filipenko, Iuliia; Zangemeister-Wittke, Uwe and Huwiler, Andrea

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1431-6730

Publisher:

De Gruyter

Language:

English

Submitter:

Debora Scherrer

Date Deposited:

23 Feb 2016 09:01

Last Modified:

13 Oct 2016 14:31

Publisher DOI:

10.1515/hsz-2014-0289

PubMed ID:

25781541

BORIS DOI:

10.7892/boris.76763

URI:

https://boris.unibe.ch/id/eprint/76763

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