Substrate-Induced Up-Regulation of Aldose Reductase by Methylglyoxal, a Reactive Oxoaldehyde Elevated in Diabetes
Methylglyoxal (MG), a reactive dicarbonyl produced during glucose metabolism, induced a dose- and time-dependent increase in aldose reductase (AR) mRNA level in rat aortic smooth muscle cells (SMCs). AR has been implicated in the pathogenesis of diabetic complications, whereas the clinical efficacy...
Saved in:
Published in | Molecular pharmacology Vol. 61; no. 5; pp. 1184 - 1191 |
---|---|
Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Pharmacology and Experimental Therapeutics
01.05.2002
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | Methylglyoxal (MG), a reactive dicarbonyl produced during glucose metabolism, induced a dose- and time-dependent increase
in aldose reductase (AR) mRNA level in rat aortic smooth muscle cells (SMCs). AR has been implicated in the pathogenesis of
diabetic complications, whereas the clinical efficacy of AR inhibitors has not been unequivocally proven. The enzyme catalyzes
the reduction of glucose in the polyol pathway, as well as that of MG, which is known to be a preferred substrate of AR. A
maximum of 4.5-fold induction of AR mRNA by MG was accompanied by elevated enzyme activity and protein levels and was completely
abolished in the presence of cycloheximide or actinomycin D. Pretreatment of SMCs with N -acetyl- l -cysteine significantly suppressed the MG-induced AR expression, whereas dl -buthionine-( S,R )-sulfoximine further augmented the MG-induced increase in AR mRNA level. Intracellular levels of reactive oxygen species
determined using 2â²,7â²-dichlorofluorescein diacetate were significantly elevated in SMCs treated with MG, suggesting the involvement
of oxidative stress in this process. However, inconsistent with our previous findings on oxidative stress-induced up-regulation
of AR, the inhibition of extracellular signal-regulated kinase by 2â²-amino-3â²-methoxyflavone (PD98059) did not affect MG-induced
AR expression, whereas blockade of the p38 mitogen-activated protein kinase pathway by 4-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl)
imidazol (SB203580) significantly suppressed the induction. The cytotoxic effect of MG on SMCs was significantly enhanced
in the presence of the AR inhibitor ponalrestat, indicating a protective role of AR against MG-induced cell damage. Taken
together, these observations indicated that substrate-induced induction of AR by MG during hyperglycemic conditions may hinder
vascular remodeling and accelerate the development of vascular lesions in diabetes. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0026-895X 1521-0111 |
DOI: | 10.1124/mol.61.5.1184 |