title: Gold-quercetin nanoparticles prevent metabolic endotoxemia-induced kidney injury by regulating TLR4/NF-κB signaling and Nrf2 pathway in high fat diet fed mice.
abstract: High-fat diet-induced metabolic syndrome followed by chronic kidney disease caused by intestinal endotoxemia have received extensive attention. Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) and oxidative stress-related Nrf2/Keap1 were regarded as the key target points involved in metabolic inflammation and kidney injury. However, the molecular mechanism of interaction between TLR4/NF-κB and Nrf2 activation in high-fat diet-induced renal injury is not absolutely understood. Quercetin, a natural product, has been reported to possess antitumor and anti-inflammatory effects. In this regard, this study attempted to prepare poly(d,l-lactide-co-glycolide)-loaded gold nanoparticles precipitated with quercetin (GQ) to investigate the anti-inflammatory and anti-oxidative stress effects in high-fat diet-induced kidney failure. For this study, C57BL/6 mice fed fat-rich fodder were used as the metabolic syndrome model to evaluate the protective effects of GQ on kidney injury and to determine whether TLR4/NF-κB and Nrf2 pathways were associated with the process. Moreover, histological examinations, enzyme-linked immunosorbent assay, Western blot, and basic blood tests and systemic inflammation-related indicators were used to investigate the inhibitory effects of GQ and underlying molecular mechanism by which it may reduce renal injury. Of note, podocyte injury was found to participate in endotoxin-stimulated inflammatory response. TLR4/NF-κB and Nrf2 pathways were upregulated with high-fat diet intake in mice, resulting in reduction of superoxide dismutase activity and increase in superoxide radical, H2O2, malondialdehyde, XO, XDH, and XO/XDH ratio. In addition, upregulation of TLR4/NF-κB and oxidative stress by endotoxin were observed in vitro, which were suppressed by GQ administration, ultimately alleviating podocyte injury. These findings indicated that GQ could restore the metabolic disorders caused by high-fat diet, which suppresses insulin resistance, lipid metabolic imbalance, and proinflammatory cytokine production. Also, it may prevent kidney injury by inhibition of TLR4/NF-κB and oxidative stress, further increasing superoxide dismutase activity.
authors.affiliation: Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing; College of Engineering and Applied Sciences, Nanjing University, Nanjing.
authors.forename: Min-Xuan
authors.initials: MX
authors.lastname: Xu
authors.affiliation: Department of Urology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang.
authors.forename: Ming
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Nephrology, Huai'an First People's Hospital, Nanjing Medical University, Jiangsu, People's Republic of China.
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Yang
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D059305:Diet, High-Fat; D019446:Endotoxemia / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006046:Gold / Q000737:chemistry*; D007249:Inflammation / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry*; D018384:Oxidative Stress / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010976:Platelet Count; D050199:Podocytes / Q000187:drug effects / Q000473:pathology; D011794:Quercetin / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects*; D013482:Superoxide Dismutase / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; D051197:Toll-Like Receptor 4; D006046:Gold; D011794:Quercetin; D013482:Superoxide Dismutase
keywords: Nrf2; TLR4/NF-κB; gold-quercetin nanoparticles; kidney injury; podocytes