PMID- 31619255 OWN - NLM STAT- MEDLINE DCOM- 20200623 LR - 20200623 IS - 1743-8977 (Electronic) IS - 1743-8977 (Linking) VI - 16 IP - 1 DP - 2019 Oct 16 TI - Inhaled gold nanoparticles cause cerebral edema and upregulate endothelial aquaporin 1 expression, involving caveolin 1 dependent repression of extracellular regulated protein kinase activity. PG - 37 LID - 10.1186/s12989-019-0324-2 [doi] LID - 37 AB - BACKGROUND: Gold nanoparticles (Au-NPs) have extensive applications in electronics and biomedicine, resulting in increased exposure and prompting safety concerns for human health. After absorption, nanoparticles enter circulation and effect endothelial cells. We previously showed that exposure to Au-NPs (40-50 nm) collapsed endothelial tight junctions and increased their paracellular permeability. Inhaled nanoparticles have gained significant attention due to their biodistribution in the brain; however, little is known regarding their role in cerebral edema. The present study investigated the expression of aquaporin 1 (AQP1) in the cerebral endothelial cell line, bEnd.3, stimulated by Au-NPs. RESULTS: We found that treatment with Au-NPs induced AQP1 expression and increased endothelial permeability to water. Au-NP exposure rapidly boosted the phosphorylation levels of focal adhesion kinase (FAK) and AKT, increased the accumulation of caveolin 1 (Cav1), and reduced the activity of extracellular regulated protein kinases (ERK). The inhibition of AKT (GDC-0068) or FAK (PF-573228) not only rescued ERK activity but also prevented AQP1 induction, whereas Au-NP-mediated Cav1 accumulation remained unaltered. Neither these signaling molecules nor AQP1 expression responded to Au-NPs while Cav1 was silenced. Inhibition of ERK activity (U0126) remarkably enhanced Cav1 and AQP1 expression in bEnd.3 cells. These data demonstrate that Au-NP-mediated AQP1 induction is Cav1 dependent, but requires the repression on ERK activity. Mice receiving intranasally administered Au-NPs displayed cerebral edema, significantly augmented AQP1 protein levels; furthermore, mild focal lesions were observed in the cerebral parenchyma. CONCLUSIONS: These data suggest that the subacute exposure of nanoparticles might induce cerebral edema, involving the Cav1 dependent accumulation on endothelial AQP1. FAU - Chen, Ching-Yi AU - Chen CY AD - Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 110, Taiwan. AD - Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan. AD - School of Pharmacy, Taipei Medical University, Taipei, Taiwan. FAU - Liao, Po-Lin AU - Liao PL AD - School of Pharmacy, Taipei Medical University, Taipei, Taiwan. AD - Institute of Food Safety and Health Risk Assessment, School of Pharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan. FAU - Tsai, Chi-Hao AU - Tsai CH AD - Institute of Food Safety and Health Risk Assessment, School of Pharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan. FAU - Chan, Yen-Ju AU - Chan YJ AD - Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 110, Taiwan. AD - Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan. FAU - Cheng, Yu-Wen AU - Cheng YW AD - School of Pharmacy, Taipei Medical University, Taipei, Taiwan. FAU - Hwang, Ling-Ling AU - Hwang LL AD - Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 110, Taiwan. AD - Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan. FAU - Lin, Kuan-Hung AU - Lin KH AD - Institute of Biomedical Sciences, Mackay Medical College, New Taipei city, Taiwan. FAU - Yen, Ting-Ling AU - Yen TL AD - Department of Medical Research, Cathay General Hospital, Taipei, 22174, Taiwan. FAU - Li, Ching-Hao AU - Li CH AUID- ORCID: 0000-0003-3183-406X AD - Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 110, Taiwan. bros22@tmu.edu.tw. AD - Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan. bros22@tmu.edu.tw. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20191016 PL - England TA - Part Fibre Toxicol JT - Particle and fibre toxicology JID - 101236354 RN - 0 (Caveolin 1) RN - 059QF0KO0R (Water) RN - 146410-94-8 (Aquaporin 1) RN - 7440-57-5 (Gold) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) SB - IM EIN - Part Fibre Toxicol. 2019 Nov 18;16(1):43. PMID: 31739798 MH - Animals MH - Aquaporin 1/*metabolism MH - Brain Edema/*chemically induced/metabolism MH - Caveolin 1/*metabolism MH - Cell Line MH - Cell Survival/drug effects MH - Dose-Response Relationship, Drug MH - Endothelial Cells/*drug effects/metabolism MH - Extracellular Signal-Regulated MAP Kinases/*antagonists & inhibitors MH - Gold/chemistry/*toxicity MH - Humans MH - Inhalation Exposure/*adverse effects MH - Male MH - Metal Nanoparticles/chemistry/*toxicity MH - Mice MH - Mice, Inbred ICR MH - Particle Size MH - Surface Properties MH - Water/metabolism PMC - PMC6796418 OTO - NOTNLM OT - Aquaporin 1 OT - Caveolin 1 OT - ERK OT - Edema OT - Endothelial cell OT - Gold nanoparticle COIS- The authors declare that they have no competing interests. EDAT- 2019/10/18 06:00 MHDA- 2020/06/24 06:00 PMCR- 2019/10/16 CRDT- 2019/10/18 06:00 PHST- 2019/07/19 00:00 [received] PHST- 2019/09/27 00:00 [accepted] PHST- 2019/10/18 06:00 [entrez] PHST- 2019/10/18 06:00 [pubmed] PHST- 2020/06/24 06:00 [medline] PHST- 2019/10/16 00:00 [pmc-release] AID - 10.1186/s12989-019-0324-2 [pii] AID - 324 [pii] AID - 10.1186/s12989-019-0324-2 [doi] PST - epublish SO - Part Fibre Toxicol. 2019 Oct 16;16(1):37. doi: 10.1186/s12989-019-0324-2.