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J. Biol. Chem., Vol. 279, Issue 33, 34343-34352, August 13, 2004

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Bimodal Effect of Advanced Glycation End Products on Mesangial Cell Proliferation Is Mediated by Neutral Ceramidase Regulation and Endogenous Sphingolipids^*

Karen Geoffroy, Nicolas Wiernsperger, Michel Lagarde, and Samer El Bawab

From the Diabetic Microangiopathy Research Unit, MERCK Santé/INSERM UMR 585/INSA-Lyon, Bldg. L. Pasteur, 20 Ave. A. Einstein, 69621 Villeurbanne, France

Advanced glycation end-products (AGE) are generated by chronic hyperglycaemia and may cause diabetic microvascular complications such as diabetic nephropathy. Many factors influence the development of diabetic nephropathy; however, dysregulation of mesangial cell (MC) proliferation appears to play an early and crucial role. In this study, we investigated the effects of AGE on rat MC proliferation and the involvement of sphingolipids in the AGE response. Results show a bimodal effect of AGE on MC proliferation. Thus, low AGE concentrations (<1 µM) induced a significant increase (+26%) of MC proliferation, whereas higher concentrations (10 µM) markedly reduced it (–24%). In parallel, AGE exerted biphasic effects on neutral ceramidase expression and activity. Low AGE concentrations increased neutral ceramidase activity and expression, whereas high AGE concentrations showed opposite effects. Surprisingly, neutral ceramidase modulation did not result in changes of ceramide levels. However, the AGE (10 µM)-inhibitory effect on MC proliferation was associated with accumulation of sphingosine and was specifically prevented by blocking glucosylceramide synthesis, suggesting that the high AGE concentration effects are mediated by sphingosine and/or glycolipids. On the other hand, treatment of cells with low AGE concentrations led to an increase of sphingosine kinase activity and sphingosine-1-phosphate production that drove the increase of MC proliferation. Interestingly, in glomeruli isolated from streptozotocin-diabetic rats, a time-dependent modulation of ceramidase activity was observed as compared with controls. These results suggest that AGE regulate MC growth by modulating neutral ceramidase and endogenous sphingolipids.

Received for publication, March 24, 2004 , and in revised form, May 24, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. E-mail: samer.elbawab{at}merck.fr.

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