Biochem. J. (2005) 388
(537–544) (Printed in Great Britain)
Glucosamine induces cell-cycle arrest and hypertrophy of mesangial cells: implication of gangliosides
Elodie MASSON, Nicolas WIERNSPERGER, Michel LAGARDE and Samer El BAWAB1
Diabetic Microangiopathy Research Unit, MERCK Santé/INSERM UMR 585, INSA Lyon (Institut National des Sciences Appliquées de Lyon), Louis Pasteur Bldg, 69621 Villeurbanne Cedex, France
Alterations in proliferation and hypertrophy of renal mesangial cells are typical features of diabetic nephropathy. The HP (hexosamine pathway) has been proposed as a biochemical hypothesis to explain microvascular alterations due to diabetic nephropathy; however, involvement of HP in the regulation of mesangial cell growth or hypertrophy has been poorly studied. Although gangliosides are known to regulate cell proliferation, their potential role in mesangial cell-growth perturbations has hardly been explored. In the present study, we investigated the effects of the HP activation, mimicked by GlcN (glucosamine) treatment, on mesangial cell growth and hypertrophy and the potential implication of gangliosides in these processes. Our results indicate that GlcN induced hypertrophy of mesangial cells, as measured by an increase in the protein/cell ratio, and it caused cell-cycle arrest by an increase in the expression of cyclin-dependent kinase inhibitor p21Waf1/Cip1. Furthermore, GlcN treatment resulted in a massive increase in the levels of gangliosides GM2 and GM1. Treatment of cells with exogenous GM2 and GM1 reproduced the effects of 0.5 mM GlcN on p21Waf1/Cip1 expression, cell-cycle arrest and hypertrophy, suggesting that gangliosides GM2 and GM1 are probably involved in mediating GlcN effects. These results document a new role of the HP in the regulation of mesangial cell growth and hypertrophy. They also suggest a potential new mechanism of action of the HP through modulation of ganglioside levels.
Key words: diabetic nephropathy, ganglioside, growth arrest, hexosamine pathway, hypertrophy, mesangial cell.
Abbreviations used: CDKI, cyclin-dependent kinase inhibitor; DN, diabetic nephropathy; GFAT, glutamine:fructose 6-phosphate amidotransferase; GlcN, glucosamine; HP, hexosamine pathway; HPTLC, high-performance TLC; RMC, renal mesangial cells; TGFb, transforming growth factor b.
1To whom correspondence should be addressed (email samer.elbawab@merck.fr).
Received 3 September 2004/10 January 2005; accepted 17 January 2005
Published as BJ Immediate Publication 17 January 2005, DOI 10.1042/BJ20041506
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