Knockdown of glyoxalase 1 mimics diabetic nephropathy in nondiabetic mice.
Authors Giacco F, Du X, D'Agati VD, Milne R, Sui G, Geoffrion M, Brownlee M
Submitted By Michael Brownlee on 6/2/2014
Status Published
Journal Diabetes
Year 2014
Date Published 1/1/2014
Volume : Pages 63 : 291 - 299
PubMed Reference 24062246
Abstract Differences in susceptibility to diabetic nephropathy (DN) between mouse strains
with identical levels of hyperglycemia correlate with renal levels of oxidative
stress, shown previously to play a central role in the pathogenesis of DN.
Susceptibility to DN appears to be genetically determined, but the critical
genes have not yet been identified. Overexpression of the enzyme glyoxalase 1
(Glo1), which prevents posttranslational modification of proteins by the
glycolysis-derived a-oxoaldehyde, methylglyoxal (MG), prevents
hyperglycemia-induced oxidative stress in cultured cells and model organisms. In
this study, we show that in nondiabetic mice, knockdown of Glo1 increases to
diabetic levels both MG modification of glomerular proteins and oxidative
stress, causing alterations in kidney morphology indistinguishable from those
caused by diabetes. We also show that in diabetic mice, Glo1 overexpression
completely prevents diabetes-induced increases in MG modification of glomerular
proteins, increased oxidative stress, and the development of diabetic kidney
pathology, despite unchanged levels of diabetic hyperglycemia. Together, these
data indicate that Glo1 activity regulates the sensitivity of the kidney to
hyperglycemic-induced renal pathology and that alterations in the rate of MG
detoxification are sufficient to determine the glycemic set point at which DN
occurs.


Investigators with authorship
NameInstitution
Michael BrownleeAlbert Einstein College of Medicine

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