Glucosamine induces cell-cycle arrest and hypertrophy of mesangial cells: implication of gangliosides.
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 p21(Waf1/Cip1). Furthermore, GlcN treatment resulted in a massive increase in the levels of gangliosides G(M2) and G(M1). Treatment of cells with exogenous G(M2) and G(M1) reproduced the effects of 0.5 mM GlcN on p21(Waf1/Cip1) expression, cell-cycle arrest and hypertrophy, suggesting that gangliosides G(M2) and G(M1) 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.
Masson
Elodie
E
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.
Wiernsperger
Nicolas
N
Lagarde
Michel
M
El Bawab
Samer
S
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D005677:G(M1) Ganglioside / Q000378:metabolism / Q000502:physiology*; D005678:G(M2) Ganglioside / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation; D005920:Glomerular Mesangium / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005944:Glucosamine / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
C493958:Cdkn1a protein, rat; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D005678:G(M2) Ganglioside; D005677:G(M1) Ganglioside; D005944:Glucosamine