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Ceramide Kinase Contributes to Proliferation but Not to Prostaglandin E2 Formation in Renal Mesangial Cells and Fibroblasts

Ceramide Kinase Contributes to Proliferation but Not to Prostaglandin E2 Formation in Renal Mesangial Cells and Fibroblasts

Oleksandr Pastukhov, Stephanie Schwalm, Isolde Römer, Uwe Zangemeister-Wittke, Josef Pfeilschifter, Andrea Huwiler

Cell Physiol Biochem. 2014;34(1):119-33.

PMID: 24977486

Abstract:

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 [(3)H]-thymidine incorporation into DNA, [(3)H]-arachidonic acid release, prostaglandin E2 (PGE2) 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 PGE2 synthesis. Similarly, proliferation but not arachidonic acid release or PGE2 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 PGE2 formation of renal mesangial cells and fibroblasts, and suggest that targeted CerK inhibition has potential for treating mesangioproliferative kidney diseases.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP362003836	NVP-231		362003-83-6	Price

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