Dicarbonyl-mediated AGEing and diabetic kidney disease
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REVIEW
Dicarbonyl‑mediated AGEing and diabetic kidney disease Alexandra Dimitropoulos1 · Carlos J. Rosado1 · Merlin C. Thomas1 Received: 4 December 2019 / Accepted: 5 March 2020 © Italian Society of Nephrology 2020
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. Keywords Advanced glycation end-products · AGEs dicarbonyl · Methylglyoxal · MG · Glyoxalase · GLO1 · Diabetic kidney disease · DKD · Receptor for advanced glycation end-products · RAGE
Introduction The toxic effects of chronic hyperglycaemia on the kidney are not mediated directly by extracellular glucose. Rather, increased glucose flux into vulnerable renal cells results in the generation of reactive intermediates, which are the essential driving force of glucotoxicity [1]. The two most important of these are reactive oxygen species (ROS) and α, β-dicarbonyls, such as the methylglyoxal (MG), glyoxal and 3-deoxyglucosone (3-DG). Just as diabetes leads to oxidative stress, diabetes may also be considered as a state of dicarbonyl stress, in so far as the generation of dicarbonyls is increased, while protective pathways including endogenous clearance mechanisms are reduced. Together this means that diabetes is associated with elevated levels of dicarbonyls, and Advanced Glycation End-products (AGEs) as a result of exposure to them. There are now strong experimental and clinical data linking reactive dicarbonyls to the development and progression of all diabetic complications, including * Merlin C. Thomas [email protected] 1
Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia
nephropathy. Their importance as downstream mediators of diabetic kidney disease (DKD) has been demonstrated in studies using direct exposure to dicarbonyls to generate lesions in the kidney similar to those seen in DKD, even in the absence of hyperglycaemia [2−4]. Furth
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