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

Sun Y¹, Guo F², Zou Z³, Li C⁴, Hong X^5,6,7, Zhao Y⁸, Wang C⁹, Wang H¹⁰, Liu H¹¹, Yang P¹², Han Z¹³, Liu K¹⁴, Kuba K¹⁵, Song B¹⁶, Gao J¹⁷, Mo Z¹⁸, Li D¹⁹, Li B²⁰, Li Q²¹, Zhong N²², Wang C²³, Penninger JM²⁴, Jiang C^25,26,27

Part Fibre Toxicol. 2015 Mar 7;12:4. PMID:25890286 [PubMed-in process] PMCID: PMC4395934

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: