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Dicarbonyl-mediated AGEing and diabetic kidney disease

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Abstract

Increased glycolytic flux into the diabetic kidney, combined with glycolytic inefficiencies introduced by oxidative stress, acts to increase the generation of triose-phosphate intermediates, which spontaneously degrade to form methylglyoxal. At the same time, the glyoxalase-catalysed pathway that degrades excess methylglyoxal is impaired. The resulting dicarbonyl stress increases the accumulation of Advanced Glycation End-products (AGEs), as highly reactive dicarbonyls modify proteins, DNA, phospholipids and even small molecules like glutathione and nitric oxide. The resulting molecular dysfunction, contributes to the development and progression of kidney disease in diabetes. The importance of the dicarbonyls in diabetic kidney disease is clearly demonstrated by the reno-protective benefits of structurally-disparate dicarbonyl scavengers in experimental studies. Equally, modulating the glyoxalase pathway is able to alter both dicarbonyl generation and renal dysfunction in the presence and absence of hyperglycaemia. However, beyond improving glycemia control and reducing oxidative stress, an effective way to attenuate dicarbonyl-mediated damage in patients with diabetic kidney disease remains an elusive goal.

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Acknowledgements

MCT is supported by an NHMRC Senior Research Fellowship. AD is a recipient of an Australian Government RTP stipend.

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Authors and Affiliations

  1. Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia

    Alexandra Dimitropoulos, Carlos J. Rosado & Merlin C. Thomas

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  1. Alexandra Dimitropoulos
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  2. Carlos J. Rosado
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  3. Merlin C. Thomas
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Correspondence to Merlin C. Thomas.

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MCT and CJR have filed patents pertaining to the Receptor of Advanced Glycation End-products (RAGE). AD has no conflict of interest.

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This article is a review of the literature, and as such, its compilation or submission did not require formal informed consent from human participants and/or animals, or ethical clearance according to standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Dimitropoulos, A., Rosado, C.J. & Thomas, M.C. Dicarbonyl-mediated AGEing and diabetic kidney disease. J Nephrol 33, 909–915 (2020). https://doi.org/10.1007/s40620-020-00718-z

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