Abstract
The lipid mediator sphingosine 1-phosphate (S1P) may alter the proliferation of mesangial cells during pathophysiological processes. Here, S1P stimulated proliferation of rat mesangial cells and phosphorylation of MAPKs at subconfluent cell density. Both effects were inhibited by pertussis toxin treatment. Mesangial cells expressed several S1P receptors of the endothelial differentiation gene family: EDG-1, -3, -5, and -8. Conversely, S1P induced apoptosis at low cell density (2 x 10(4) cells/cm(2)), which was demonstrated by flow cytometry and Hoechst staining. Apoptosis was observed also in quiescent or growing cells and was not reverted by lysophosphatidic acid or platelet-derived growth factor. S1P enhanced phosphorylation of SAPKs. Incubation with [(33)P]S1P, [(3)H]S1P, and [(3)H]sphingosine demonstrated increased S1P hydrolysis, resulting in enhanced intracellular sphingosine levels and decreased S1P levels. A rise in total ceramide levels was also observed; however, ceramide did not originate from [(3)H]sphingosine, and S1P-induced apoptosis was not inhibited by fumonisin B, precluding involvement of de novo ceramide synthesis in apoptosis. Therefore, we suggest that sphingosine accumulation and decreased S1P are primarily responsible for S1P-induced apoptosis. In conclusion, incubation of low-density mesangial cells with S1P results in apoptosis, presumably due to increased S1P hydrolysis.
Highlights
Glomerular diseases are often characterized by the increasing proliferation rate of mesangial cells, responsible for altered composition of the extracellular matrix, with both mechanisms leading to progressive fibrosis [1,2,3,4]
sphingosine 1-phosphate (S1P) stimulated the proliferation of rat mesangial cells in a dose-dependent fashion
S1P-induced proliferation involved the long-term phosphorylation of the mitogen-activated protein kinase (MAPK) ERK1 and ERK2. This result is in agreement with other studies in mesangial cells where sustained activation of ERK1/2 has been related to mitogenesis induced by growth factors such as PDGF, lysophosphatidic acid (LPA), and angiotensin II [11, 39, 40]
Summary
Glomerular diseases are often characterized by the increasing proliferation rate of mesangial cells, responsible for altered composition of the extracellular matrix, with both mechanisms leading to progressive fibrosis [1,2,3,4]. Incubation of low-density mesangial cells with S1P results in apoptosis, presumably due to increased S1P hydrolysis. We tested the effect of sphingosine, which appeared to be density-dependent, resulting in stimulated thymidine incorporation at high cell density and inhibition at low cell density (Fig. 5A).
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