EGF receptor-ERK pathway is the major signaling pathway that mediates upregulation of aldose reductase expression under oxidative stress

Acceleration of the polyol pathway and enhanced oxidative stress are implicated in the pathogenesis of diabetic complications. We and others recently reported that aldose reductase (AR), the rate-limiting enzyme in the polyol pathway, was upregulated by reactive oxygen and nitrogen species in vascul...

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Bibliographic Details
Published in:Free radical biology & medicine 2001-07, Vol.31 (2), p.205-216
Main Authors: Nishinaka, Toru, Yabe-Nishimura, Chihiro
Format: Article
Language:English
Subjects:
Aldehyde Reductase - antagonists & inhibitors
Aldehyde Reductase - genetics
Aldehyde Reductase - metabolism
Aldose reductase
Animals
Cell Line
Cell Survival
Diabetes
Diabetes Complications
Diabetes Mellitus - metabolism
EGF receptor
ErbB Receptors - metabolism
Flavonoids - pharmacology
Free Radical Scavengers - pharmacology
Free radicals
Humans
Hydrogen Peroxide - pharmacology
MAP kinase
Mitogen-Activated Protein Kinases - metabolism
Muscle, Smooth, Vascular - drug effects
Muscle, Smooth, Vascular - metabolism
Oxidative Stress
Oxidized LDL
Phthalazines - pharmacology
Protein Kinases - metabolism
Quinazolines
Rats
RNA, Messenger - genetics
RNA, Messenger - metabolism
Signal Transduction
Tyrphostins - pharmacology
Up-Regulation - drug effects
Vascular smooth muscle cells
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Summary:Acceleration of the polyol pathway and enhanced oxidative stress are implicated in the pathogenesis of diabetic complications. We and others recently reported that aldose reductase (AR), the rate-limiting enzyme in the polyol pathway, was upregulated by reactive oxygen and nitrogen species in vascular smooth muscle cells. To clarify the molecular mechanisms underlying these findings, we investigated the signal transduction pathways mediating AR expression using the rat vascular smooth muscle cell line A7r5. A selective epidermal growth factor (EGF) receptor kinase inhibitor, tyrphostin AG1478, significantly suppressed the hydrogen peroxide (H 2O 2)-induced increase in AR mRNA and enzyme activity. Activation of extracellular signal-regulated protein kinase (ERK) by H 2O 2 was blunted by AG1478. PD98059, a specific inhibitor of ERK kinase (MEK1), reduced H 2O 2-induced AR expression. EGF alone elicited activation of ERK and induction of AR expression. Increased level of AR transcript was demonstrated in cells treated with oxidized low-density lipoprotein, and this increase was also suppressed by AG1478. Inhibition of p38 MAP kinase by SB203580 also partially suppressed the H 2O 2-initiated AR induction. The presence of ponalrestat, an AR inhibitor, significantly accelerated H 2O 2-induced cell death. These results suggested that AR may act as a survival factor in these cells and that the EGF receptor-ERK pathway is the major signaling pathway involved in the upregulation of AR expression under oxidative stress.
ISSN:0891-5849
1873-4596
DOI:10.1016/S0891-5849(01)00571-8