Knockdown of Glyoxalase 1 Mimics Diabetic Nephropathy in Nondiabetic Mice

  1. Michael Brownlee1,2,5
  1. 1Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY
  2. 2Department of Medicine, Albert Einstein College of Medicine, Bronx, NY
  3. 3Division of Renal Pathology, Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY
  4. 4Diabetes and Atherosclerosis Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
  5. 5Department of Pathology, Albert Einstein College of Medicine, Bronx, NY
  1. Corresponding author: Michael Brownlee, michael.brownlee{at}
  1. F.G. and X.D. contributed equally to this work.


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.


  • Received February 22, 2013.
  • Accepted September 12, 2013.

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