Cationic nanoparticles directly bind angiotensin-converting enzyme 2 and induce acute lung injury in mice

Yang Sun, Feng Guo, Zhen Zou, Chenggang Li, Xiaoxu Hong, Yan Zhao, Chenxuan Wang, Hongliang Wang, Haolin Liu, Peng Yang, Zongsheng Han, Kangtai Liu, Keiji Kuba, Bin Song, Jinming Gao, Ziyao Mo, Dangsheng Li, Bo Li, Qihan Li, Nanshan ZhongChen Wang, Josef M. Penninger, Chengyu Jiang

Research output: Contribution to journalArticlepeer-review

44 Citations (Scopus)

Abstract

Background: Nanoparticles have become a key technology in multiple industries. However, there are growing reports of the toxicity of nanomaterials to humans. In particular, nanomaterials have been linked to lung diseases. The molecular mechanisms of nanoparticle toxicity are largely unexplored. Methods: Acute lung injury was induced in wild-type mice and angiotensin-coverting enzyme 2 (ACE2) knockout mice by the intratracheal instillation of cationic polyamidoamine dendrimer (PAMAM) nanoparticles. For rescue experiments, losartan (15 mg/kg in PBS) was injected intraperitoneally 30 min before nanoparticle administration. Results: Some PAMAM nanoparticles, but not anionic PAMAM nanoparticles or carbon nanotubes, triggered acute lung failure in mice. Mechanistically, cationic nanoparticles can directly bind ACE2, decrease its activity and down-regulate its expression level in lung tissue, resulting in deregulation of the renin-angiotensin system. Gene inactivation of Ace2 can exacerbate lung injury. Importantly, the administration of losartan, which is an angiotensin II type I receptor antagonist, can ameliorate PAMAM nanoparticle-induced lung injury. Conclusions: Our data provide molecular insight into PAMAM nanoparticle-induced lung injury and suggest potential therapeutic and screening strategies to address the safety of nanomaterials.

Original languageEnglish
Article number4
JournalParticle and Fibre Toxicology
Volume12
Issue number1
DOIs
Publication statusPublished - Mar 7 2015
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Toxicology
  • Health, Toxicology and Mutagenesis

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