Knockdown of glyoxalase 1 mimics diabetic nephropathy in nondiabetic mice

Ferdinando Giacco, Xue-Liang Du, Vivette D. D'Agati, Ross Milne, Guangzhi Sui, Michele Geoffrion, Michael Brownlee

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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.

Original languageEnglish (US)
Pages (from-to)291-299
Number of pages9
JournalDiabetes
Volume63
Issue number1
DOIs
StatePublished - Jan 2014

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Diabetic Nephropathies
Pyruvaldehyde
Kidney
Oxidative Stress
Hyperglycemia
Pathology
Proteins
Glycolysis
Post Translational Protein Processing
Cultured Cells
neurotensin mimic 1
Enzymes
Genes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Giacco, F., Du, X-L., D'Agati, V. D., Milne, R., Sui, G., Geoffrion, M., & Brownlee, M. (2014). Knockdown of glyoxalase 1 mimics diabetic nephropathy in nondiabetic mice. Diabetes, 63(1), 291-299. https://doi.org/10.2337/db13-0316

Knockdown of glyoxalase 1 mimics diabetic nephropathy in nondiabetic mice. / Giacco, Ferdinando; Du, Xue-Liang; D'Agati, Vivette D.; Milne, Ross; Sui, Guangzhi; Geoffrion, Michele; Brownlee, Michael.

In: Diabetes, Vol. 63, No. 1, 01.2014, p. 291-299.

Research output: Contribution to journalArticle

Giacco, F, Du, X-L, D'Agati, VD, Milne, R, Sui, G, Geoffrion, M & Brownlee, M 2014, 'Knockdown of glyoxalase 1 mimics diabetic nephropathy in nondiabetic mice', Diabetes, vol. 63, no. 1, pp. 291-299. https://doi.org/10.2337/db13-0316
Giacco F, Du X-L, D'Agati VD, Milne R, Sui G, Geoffrion M et al. Knockdown of glyoxalase 1 mimics diabetic nephropathy in nondiabetic mice. Diabetes. 2014 Jan;63(1):291-299. https://doi.org/10.2337/db13-0316
Giacco, Ferdinando ; Du, Xue-Liang ; D'Agati, Vivette D. ; Milne, Ross ; Sui, Guangzhi ; Geoffrion, Michele ; Brownlee, Michael. / Knockdown of glyoxalase 1 mimics diabetic nephropathy in nondiabetic mice. In: Diabetes. 2014 ; Vol. 63, No. 1. pp. 291-299.
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