Knockdown of Glyoxalase 1 Mimics Diabetic Nephropathy in Nondiabetic Mice
Open Access
- 13 December 2013
- journal article
- Published by American Diabetes Association in Diabetes
- Vol. 63 (1), 291-299
- https://doi.org/10.2337/db13-0316
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 α-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.Keywords
This publication has 47 references indexed in Scilit:
- Notch signaling in diabetic nephropathyExperimental Cell Research, 2012
- Glyoxalase I Retards Renal SenescenceThe American Journal of Pathology, 2011
- Overexpression of Glyoxalase-I Reduces Hyperglycemia-induced Levels of Advanced Glycation End Products and Oxidative Stress in Diabetic RatsOnline Journal of Public Health Informatics, 2011
- Oxidative Stress and Diabetic ComplicationsCirculation Research, 2010
- Hyperglycaemia-induced impairment of endothelium-dependent vasorelaxation in rat mesenteric arteries is mediated by intracellular methylglyoxal levels in a pathway dependent on oxidative stressDiabetologia, 2010
- Excerpts From the US Renal Data System 2009 Annual Data ReportAmerican Journal of Kidney Diseases, 2010
- The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissuesProceedings of the National Academy of Sciences of the United States of America, 2009
- Reduction of Renal Superoxide Dismutase in Progressive Diabetic NephropathyJournal of the American Society of Nephrology, 2009
- Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemiaThe Journal of Experimental Medicine, 2008
- Decreasing Intracellular Superoxide Corrects Defective Ischemia-induced New Vessel Formation in Diabetic MiceOnline Journal of Public Health Informatics, 2008