Abstract
The elevated glycation of macromolecules by the reactive dicarbonyl and α-oxoaldehyde methylglyoxal (MG) has been associated with diabetes and its complications. We have identified a rare flavone, fisetin, which increases the level and activity of glyoxalase 1, the enzyme required for the removal of MG, as well as the synthesis of its essential co-factor, glutathione. It is shown that fisetin reduces two major complications of diabetes in Akita mice, a model of type 1 diabetes. Although fisetin had no effect on the elevation of blood sugar, it reduced kidney hypertrophy and albuminuria and maintained normal levels of locomotion in the open field test. This correlated with a reduction in proteins glycated by MG in the blood, kidney and brain of fisetin-treated animals along with an increase in glyoxalase 1 enzyme activity and an elevation in the expression of the rate-limiting enzyme for the synthesis of glutathione, a co-factor for glyoxalase 1. The expression of the receptor for advanced glycation end products (RAGE), serum amyloid A and serum C-reactive protein, markers of protein oxidation, glycation and inflammation, were also increased in diabetic Akita mice and reduced by fisetin. It is concluded that fisetin lowers the elevation of MG-protein glycation that is associated with diabetes and ameliorates multiple complications of the disease. Therefore, fisetin or a synthetic derivative may have potential therapeutic use for the treatment of diabetic complications.
Highlights
The complications of diabetes are the major cause of both morbidity and mortality in patients with the disease [1], [2]
To test the hypothesis that a compound such as fisetin which targets multiple pathways associated with hyperglycemia including MG-dependent protein glycation in vitro can prevent the complications of diabetes in vivo, we examined the effects of fisetin on the development of diabetic nephropathy and anxiety symptoms in the Akita mouse model of type 1 diabetes
Since elevated receptor for advanced glycation end products (RAGE) is a physiological response to both inflammation and protein glycation, we examined another indicator of inflammation, the acute phase response (APR) protein C-reactive protein (CRP), in the blood of the Akita and control mice
Summary
The complications of diabetes are the major cause of both morbidity and mortality in patients with the disease [1], [2]. Fisetin protects nerve cells in culture from assorted toxic insults including ischemia and oxidative stress. It has direct antioxidant activity and increases the level of the major intracellular antioxidant, glutathione (GSH). Fisetin can induce the transcription factor Nrf that is associated with the up-regulation of GSH metabolism and the protection of cells from toxic stress. Others have found that fisetin has anti-inflammatory activity in vitro [6], [7]. Many of these activities of fisetin have the potential to reduce the metabolic dysfunctions that are associated with diabetic complications, it is not clear which activities are relevant in vivo
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