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

Cellular Physiology and Biochemistry

关键词: Apoptosis;    Prostaglandin E2;    Mesangial cells;    Fibroblasts;    Proliferation;    M phase arrest;    Ceramide kinase;    NVP-231;   

DOI  :  10.1159/000362989

学科分类：分子生物学，细胞生物学和基因

来源: S Karger AG

【 摘 要 】

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 [³H]-thymidine incorporation into DNA, [³H]-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.

【 授权许可】

CC BY-NC-ND