Hyperglycemia Impairs Proteasome Function by Methylglyoxal

摘要: OBJECTIVE The ubiquitin-proteasome system is the main degradation machinery for intracellularly altered proteins. Hyperglycemia has been shown to increase intracellular levels of reactive dicarbonyl methylglyoxal (MGO) in cells damaged by diabetes, resulting modification proteins and alterations their function. In this study, influence MGO-derived advanced glycation end product (AGE) formation on activity proteasome was investigated vitro vivo. RESEARCH DESIGN AND METHODS AGE subunits analyzed mass spectrometry, immunoprecipitation, Western blots. Proteasome using proteasome-specific fluorogenic substrates. Experimental models included bovine retinal endothelial cells, diabetic Ins2 Akita mice, glyoxalase 1 (GLO1) knockdown streptozotocin (STZ)-injected mice. RESULTS incubation with MGO caused adduct several 20S proteasomal subunit cultured expression level catalytic not but chymotrypsin-like significantly reduced. contrast, regulatory 19S were decreased. , STZ diabetic, nondiabetic G101 also reduced 20S-β2 increased. CONCLUSIONS Hyperglycemia-induced covalently modifies proteasome, decreasing its kidney reducing polyubiquitin receptor 19S-S5a. results indicate a new link between hyperglycemia impairment cell functions.