Knockdown of Glyoxalase 1 Mimics Diabetic Nephropathy in Nondiabetic Mice
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- Ferdinando Giacco
- Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY
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- Xueliang Du
- Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY
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- Vivette D. D’Agati
- Division of Renal Pathology, Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY
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- Ross Milne
- Diabetes and Atherosclerosis Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
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- Guangzhi Sui
- Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY
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- Michele Geoffrion
- Diabetes and Atherosclerosis Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
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- Michael Brownlee
- Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY
Abstract
<jats:p>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.</jats:p>
Journal
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- Diabetes
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Diabetes 63 (1), 291-299, 2013-12-13
American Diabetes Association
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Details 詳細情報について
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- CRID
- 1362544420013259904
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- ISSN
- 1939327X
- 00121797
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- Data Source
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- Crossref