ABSTRACT
Methylglyoxal (MG) is generated from glycolytic metabolites, lipid peroxidation, glucose autooxidation and protein glycation. It is a prooxidant inducing oxidative stress and formation of advanced glycation end products (AGE). Effect of carnosine (CAR) as an antioxidant on toxicity due to MG has generated interest. In this study, rats were given incrementally increased doses (100-300 mg/kg) of MG in drinking water for ten weeks. CAR (250 mg/kg i.p.) was administered with MG. Plasma thiobarbituric reactive substances (TBARS), protein carbonyl (PC), advanced oxidation protein products (AOPP) and AGE levels were elevated by MG, and CAR decreased PC, AOPP and AGE levels. MG increased liver reactive oxygen species (ROS), TBARS, PC and AOPP levels, which were decreased by CAR. Thus, in vivo role of CAR on chronic MG administration was observed to suppress the generated hepatic and plasma oxidative stress.
Subject(s)
Advanced Oxidation Protein Products/antagonists & inhibitors , Antioxidants/pharmacology , Carnosine/pharmacology , Glycation End Products, Advanced/antagonists & inhibitors , Liver/drug effects , Pyruvaldehyde/antagonists & inhibitors , Advanced Oxidation Protein Products/agonists , Advanced Oxidation Protein Products/metabolism , Animals , Glycation End Products, Advanced/agonists , Glycation End Products, Advanced/metabolism , Injections, Intraperitoneal , Lipid Peroxidation/drug effects , Liver/metabolism , Male , Oxidative Stress/drug effects , Protein Carbonylation , Pyruvaldehyde/toxicity , Rats , Rats, Sprague-Dawley , Reactive Oxygen Species/agonists , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolism , Thiobarbituric Acid Reactive Substances/metabolismABSTRACT
Endothelial-to-mesenchymal transition (EndMT) in renal glomerular endothelial cells plays a critical role in the pathogenesis of diabetic nephropathy (DN). Furthermore, advanced oxidation protein products (AOPPs) have been shown to contribute to the progression of DN. However, whether AOPPs induce EndMT in renal glomerular endothelial cells remains unclear. Thus, we investigated the effect of AOPPs on human renal glomerular endothelial cells (HRGECs) and the mechanisms underlying the effects. Our results showed that AOPP treatment lowered the expression of vascular endothelial cadherin, CD31, and claudin 5 and induced the overexpression of α-smooth muscle actin, vimentin, and fibroblast-specific protein 1, which indicated that AOPPs induced EndMT in HRGECs. Furthermore, AOPP stimulation increased the expression of glucose-regulated protein 78 and CCAAT/enhancer-binding protein-homologous protein, which suggested that AOPPs triggered endoplasmic reticulum (ER) stress in HRGECs. Notably, the aforementioned AOPP effects were reversed following the treatment of cells with salubrinal, an inhibitor of ER stress, whereas the effects were reproduced after exposure to thapsigargin, an inducer of ER stress. Collectively, our results indicate that AOPPs trigger EndMT in HRGECs through the induction of ER stress. These findings suggest novel therapeutic strategies for inhibiting renal fibrosis by targeting ER stress.
