Long-term administration of advanced glycation end-product stimulates the activation of NLRP3 inflammasome and sparking the development of renal injury

• Published in: The Journal of nutritional biochemistry 2017-01, Vol.39, p.68-76
• Main Authors: Yeh, Wan-Ju, Yang, Hsin-Yi, Pai, Man-Hui, Wu, Chi-Hao, Chen, Jiun-Rong
• Format: Article
• Language: English
• Subjects: Advanced glycation end-products; Animals; Blood Urea Nitrogen; Creatinine - blood; Cytokines - blood; Endothelial dysfunction; Endothelial Progenitor Cells - drug effects; Endothelial Progenitor Cells - metabolism; Glycation End Products, Advanced - pharmacology; Inflammasomes - genetics; Inflammasomes - metabolism; Kidney - drug effects; Kidney - metabolism; Kidney Diseases - drug therapy; Kidney Diseases - etiology; Kidney Diseases - genetics; Mice; Mice, Inbred BALB C; Nitric Oxide - metabolism; Nitric Oxide Synthase Type III - genetics; Nitric Oxide Synthase Type III - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3 inflammasome; Oxidative Stress - drug effects; Pyruvaldehyde - pharmacology; RAGE; Reactive Oxygen Species - metabolism; Receptor for Advanced Glycation End Products - genetics; Receptor for Advanced Glycation End Products - metabolism; Renal injury; Serum Albumin, Bovine - pharmacology
• ISSN: 0955-2863; 1873-4847
• DOI: 10.1016/j.jnutbio.2016.09.014

The accumulation of advanced glycation end-products (AGEs) and the enhanced interaction of AGE with their cellular receptor (RAGE) have been implicated in the progression of chronic kidney disease. The purpose of this study was to examine whether the AGE/RAGE-induced nephrotoxic effects are associated with inflammasome activation and endothelial dysfunction. Chronic renal injury was examined in BALB/c mice by the long-term administration of carbonyl-AGE for 16 weeks. Endothelial dysfunction was detected by measuring the number of circulating endothelial progenitor cells (EPCs) and the levels of nitric oxide synthase (eNOS) and nitric oxide (NO) in kidneys. Results showed that administration of methylglyoxal–bovine serum albumin (MG-BSA) AGE accelerated renal MG, carboxyethyl lysine, carboxymethyl lysine and malondialdehyde formation and, in parallel, the levels of serum creatinine and blood urea nitrogen (BUN) were significantly increased. Expression of RAGE and NLRP3 inflammasome-related proteins (TXNIP, NLRP3, procaspase-1 and caspase-1) and IL (interleukin)-1β secretion were upregulated, whereas the levels of EPCs, eNOS and NO were lower in MG-BSA-treated mice. This induction by MG-BSA was significantly inhibited by RAGE antagonist. Our results firstly reveal a possible mechanism of AGE-mediated renal dysfunction upon NLRP3 inflammasome activation. Therapeutic blockade of RAGE may ameliorate renal and endothelial functions in subjects under high AGE burden.