a-Series gangliosides mediate the effects of advanced glycation end products on pericyte and mesangial cell proliferation: a common mediator for retinal and renal microangiopathy?
Advanced glycation end products (AGEs) are involved in the development of microvascular complications, including alterations of retinal pericyte and renal mesangial cell growth occurring during diabetic retinopathy and diabetic nephropathy, respectively. Because gangliosides are implicated in the regulation of cell proliferation, we hypothesized that AGEs could exert cellular effects in part by modulating ganglioside levels. Results of the present study indicate that AGEs caused an inhibition of both bovine retinal pericyte (BRP) and rat renal mesangial cell (RMC) proliferation, associated with an increase of a-series gangliosides consecutive to GM3 synthase activity increase and GD3 synthase activity inhibition. Similar modifications were also found in the renal cortex of diabetic db/db mice compared with controls. Treatment of BRP and RMC with exogenous a-series gangliosides decreased proliferation and blockade of a-series gangliosides with specific antibodies partially protecting the two cell types from the AGE-induced proliferation decrease. Further, inhibition of GM3 synthase using specific SiRNA partially reversed the AGE effects on mesangial cell proliferation. These results suggest that a-series gangliosides are mediators of the adverse AGE effects on BRP and RMC proliferation. They also raise the hypothesis of common mechanisms involved in the development of diabetic retinopathy and diabetic nephropathy.
Masson
Elodie
E
Diabetic Microangiopathy Research Unit, MERCK Santé-INSERM U585, INSA-Lyon, Louis Pasteur Bldg., 69621 Villeurbanne Cedex, France.
Troncy
Lysiane
L
Ruggiero
Daniel
D
Wiernsperger
Nicolas
N
Lagarde
Michel
M
El Bawab
Samer
S
D000818:Animals; D002417:Cattle; D002455:Cell Division / Q000187:drug effects*; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000503:physiopathology* / Q000517:prevention & control; D003930:Diabetic Retinopathy / Q000503:physiopathology* / Q000517:prevention & control; D004195:Disease Models, Animal; D005677:G(M1) Ganglioside / Q000502:physiology; D005679:G(M3) Ganglioside / Q000502:physiology; D005732:Gangliosides / Q000502:physiology*; D005920:Glomerular Mesangium / Q000166:cytology* / Q000187:drug effects; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007672:Kidney Cortex / Q000503:physiopathology; D051379:Mice; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology*; D020286:Pericytes / Q000166:cytology* / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D012171:Retinal Vessels / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D012799:Sialyltransferases / Q000235:genetics
D005679:G(M3) Ganglioside; D005732:Gangliosides; D017127:Glycation End Products, Advanced; D034741:RNA, Small Interfering; D005677:G(M1) Ganglioside; D012799:Sialyltransferases; C021343:haematoside synthetase