Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products: inhibitory effect of gliclazide.

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Mamputu JC, Renier G

Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products: inhibitory effect of gliclazide.

Diabetes Obes Metab. 2004 Mar;6(2):95-103.

PubMed ID

14746574 [ View in PubMed

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Abstract

AIM: We have previously demonstrated that advanced glycation end products (AGEs) stimulate bovine retinal endothelial cell (BREC) proliferation through induction of vascular endothelial growth factor (VEGF) production by these cells. We have also shown that gliclazide, a sulfonylurea which decreases oxidative stress, inhibits this effect. The aim of the present study was to characterize the signalling pathways involved in AGE-induced BREC proliferation and VEGF production and mediating the inhibitory effect of gliclazide on these biological events. METHODS: BRECs were treated or not treated with AGEs in the presence or absence of gliclazide, antioxidants, protein kinase C (PKC), mitogen-activated protein kinase (MAPK) or nuclear factor-kappaB (NF-kappaB) inhibitors. BREC proliferation was assessed by measuring [3H]-thymidine incorporation into DNA. Activation of PKC, MAPK and NF-kappaB signal transduction pathways and determination of VEGF expression were assessed by Western blot analysis using specific antibodies. MAPK activity was also determined by an in vitro kinase assay. RESULTS: Treatment of BRECs with AGEs significantly increased cell proliferation and VEGF expression. AGEs induced PKC-beta translocation, extracellular signal-regulated protein kinase 1/2 and NF-kappaB activation in these cells. Pharmacological inhibition of these signalling pathways abolished AGE effects on cell proliferation and VEGF expression. Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N-acetyl-l-cysteine resulted in a significant decrease in AGE-induced activation of PKC-, MAPK- and NF-kappaB-signalling pathways. CONCLUSIONS: Our results demonstrate the involvement of PKC, MAPK and NF-kappaB in AGE-induced BREC proliferation and VEGF expression. Gliclazide inhibits BREC proliferation by interfering with these intracellular signal transduction pathways.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Gliclazide	Vascular endothelial growth factor A	Protein	Humans	Unknown	Other/unknown	Details