title: Silver nanoparticles-mediated G2/M cycle arrest of renal epithelial cells is associated with NRF2-GSH signaling.
abstract: Silver nanoparticles (nAg) are known to evoke reactive oxygen species (ROS) generation and consequent cell damage. The transcription factor NF-E2-related factor 2 (NRF2) controls both the basal and inducible expression of multiple antioxidant genes. This study was aimed to investigate the role of NRF2 in nAg-induced renal epithelial cell damage. nAg treatment intensified DNA damage and G2/M cell cycle arrest by nAg in NRF2 knockdown HK-2 (NRF2i) compared with the control cells. As a signaling mechanism associated with nAg-mediated growth arrest, the levels of phospho-CDC25C and phospho-CDC2 were significantly increased in NRF2i. Target gene analysis revealed that nAg-mediated increase in γ-glutamate cysteine ligase expression is NRF2-dependent: nAg-treated NRF2i showed a reduction in glutathione (GSH) content and elevation in ROS level in comparison with the control cells. Additionally, pretreatment of N-acetylcystein in nAg-treated NRF2i alleviated ROS-mediated DNA damage and G2/M cell cycle arrest, while GSH depletion exacerbated DNA damage and cell cycle arrest in the control cells. Taken together, these results suggest that NRF2-mediated GSH increase plays a protective role in nAg-induced DNA damage and subsequent G2/M cell cycle arrest in human renal epithelial cells.
authors.affiliation: College of Oriental Medicine, Daegu Haany University, Gyeongsan-si, Gyeongsangbuk-do 712-715, Republic of Korea.
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Kang
authors.forename: Young Joon
authors.initials: YJ
authors.lastname: Lee
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Lee
authors.forename: Mi-Kyoung
authors.initials: MK
authors.lastname: Kwak
mesh_terms: D015153:Blotting, Western; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D004396:Coloring Agents; D004249:DNA Damage; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects*; D005822:Genetic Vectors; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D015162:Micronucleus Tests; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000502:physiology*; D053758:Nanoparticles / Q000633:toxicity*; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012834:Silver / Q000633:toxicity*; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D004396:Coloring Agents; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts; D013844:Thiazoles; D012834:Silver; C022616:thiazolyl blue; D005978:Glutathione