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HIGH GLUCOSE-INDUCED INHIBITION OF 2-DEOXYGLUCOSE UPTAKE IS MEDIATED BY cAMP, PROTEIN KINASE C, OXIDATIVE STRESS AND MITOGEN-ACTIVATED PROTEIN KINASES IN MOUSE EMBRYONIC STEM CELLS

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SUMMARY



Abnormally high glucose levels may play an important role in early embryo development and function. In the present study, we investigated the effect of high glucose on 2-deoxyglucose (2-DG) uptake and its related signalling pathway in mouse embryonic stem (ES) cells.



2-Deoxyglucose uptake was maximally inhibited by 25 mmol/L glucose after 24 h treatment. However, 25 mmol/L mannitol and dextran did not affect 2-DG uptake. Indeed, 25 mmol/L glucose decreased GLUT-1 mRNA and protein levels. The glucose (25 mmol/L)-induced inhibition of 2-DG uptake was blocked by pertussis toxin (a Gi-protein inhibitor; 2 ng/mL), SQ 22536 (an adenylate cyclase inhibitor; 10-6 mol/L) and the protein kinase (PK) A inhibitor myristoylated PKI amide-(14–22) (10-6 mol/L). Indeed, 25 mmol/L glucose increased intracellular cAMP content.



Furthermore, 25 mmol/L glucose-induced inhibition of 2-DG uptake was prevented by 10-4 mol/L neomycin or 10-6 mol/L U 73122 (phospholipase C (PLC) inhibitors) and staurosporine or bisindolylmaleimide I (protein kinase (PK) C inhibitors). At 25 mmol/L, glucose increased translocation of PKC from the cytoplasmic fraction to the membrane fraction. The 25 mmol/L glucose-induced inhibition of 2-DG uptake and GLUT-1 protein levels was blocked by SQ 22536, bisindolylmaleimide I or combined treatment. In addition, 25 mmol/L glucose increased cellular reactive oxygen species and the glucose-induced inhibition of 2-DG uptake were blocked by the anti-oxidants N-acetylcysteine (NAC; 10-5 mol/L) or taurine (2 ¥ 10-3 mol/L).



Glucose (25 mmol/L) activated p38 mitogen-activated protein kinase (MAPK) and p44/42 MAPK. Staurosporine (10-6 mol/L), NAC (10-5 mol/L) and PD 98059 (10-7 mol/L) attenuated the phosphorylation of p44/42 MAPK. Both SB 203580 (a p38 MAPK inhibitor; 10-7 mol/L) and PD 98059 (a p44/42 MAPK inhibitor; 10-7 mol/L) blocked 25 mmol/L glucose-induced inhibition of 2-DG uptake.



In conclusion, high glucose inhibits 2-DG uptake through cAMP, PLC/PKC, oxidative stress or MAPK in mouse ES cells.
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Keywords: 2-deoxyglucose uptake; cAMP; embryonic stem cell; mitogen-activated protein kinase; oxidative stress; phospholipase C; protein kinase C

Document Type: Research Article

Publication date: March 1, 2006

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