Journal
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
Volume 34, Issue 1, Pages 119-133Publisher
KARGER
DOI: 10.1159/000362989
Keywords
Ceramide kinase; NVP-231; Mesangial cells; Fibroblasts; Proliferation; M phase arrest; Apoptosis; Prostaglandin E-2
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Funding
- German Research Foundation [SPP1267/2]
- Swiss National Science Foundation [310030_135619]
- Swiss National Science Foundation (SNF) [310030_135619] Funding Source: Swiss National Science Foundation (SNF)
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Background/Aims: Ceramide kinase (CerK) catalyzes the generation of the sphingolipid ceramide-1-phosphate (C1P) which regulates various cellular functions including cell growth and death, and inflammation. Here, we used a novel catalytic inhibitor of CerK, NVP-231, and CerK knockout cells to investigate the contribution of CerK to proliferation and inflammation in renal mesangial cells and fibroblasts. Methods: Cells were treated with NVP-231 and [H-3]-thymidine incorporation into DNA, [H-3]-arachidonic acid release, prostaglandin E-2 (PGE(2)) synthesis, cell cycle distribution, and apoptosis were determined. Results: Treatment of rat mesangial cells and mouse renal fibroblasts with NVP-231 decreased DNA synthesis, but not of agonist-stimulated arachidonic acid release or PGE(2) synthesis. Similarly, proliferation but not a rachidonic acid release or PGE(2) synthesis was reduced in CERK knockout renal fibroblasts. The anti proliferative effect of NVP-231 on mesangial cells was due to M phase arrest as determined using the mitosis markers phospho-histone H3, cdc2 and polo-like kinase-1, and induction of apoptosis. Moreover, loss of CerK sensitized cells towards stress induced apoptosis. Conclusions: Our data demonstrate that CerK induces proliferation but not PGE(2) formation of renal mesangial cells and fibroblasts, and suggest that targeted CerK inhibition has potential for treating mesangioproliferative kidney diseases. Copyright (C) 2014 S. Karger AG, Basel
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