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

ABSTRACT: 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.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.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.Our data provide molecular insight into PAMAM nanoparticle-induced lung injury and suggest potential therapeutic and screening strategies to address the safety of nanomaterials.

SUBMITTER: Sun Y

PROVIDER: S-EPMC4395934 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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

Sun Yang Y Guo Feng F Zou Zhen Z Li Chenggang C Hong Xiaoxu X Zhao Yan Y Wang Chenxuan C Wang Hongliang H Liu Haolin H Yang Peng P Han Zongsheng Z Liu Kangtai K Kuba Keiji K Song Bin B Gao Jinming J Mo Ziyao Z Li Dangsheng D Li Bo B Li Qihan Q Zhong Nanshan N Wang Chen C Penninger Josef M JM Jiang Chengyu C

Particle and fibre toxicology 20150307

<h4>Background</h4>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.<h4>Methods</h4>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) ...[more]

PMID: 25890286

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Project description:Evolution of glomerulonephritis (GN) to tubulointerstitial disease is a universal antecedent to the development of chronic kidney disease (CKD). There is also evidence that angiotensin converting enzyme (ACE) inhibition may attenuate the development of CKD in some forms of glomerulonephritis. We tested the role of ACE inhibition in a model of GN in which complement-dependent tubulointerstitial disease develops. GN was induced in C57BL/6 mice with intraperitoneal injections of horse spleen apoferritin (HSA) using lipopolysaccharide (LPS) as an adjuvant. Four groups of six animals were studied: saline-injected control mice treated with captopril or water, and GN mice treated with captopril or water. GN developed in all HSA-treated animals. In those receiving captopril, however, proteinuria (albumin/creatinine ratio) was significantly reduced by captopril treatment. Array screening was used to examined the expression of collagen-related genes and determine if these effects could be mediated by regulation of collagen genes. Six genes were identified for further analysis by quantitative RT-PCR. This model demonstrates that tubulointerstitial disease can be attenuated by ACE inhibition, with clinical, histologic, and gene expression measures. All protocols were approved by the Institutional Animal Care and Use Committee at SUNY Upstate Medical University. We employed four groups of six mice each: saline-injected control mice with and without captopril, and GN with and without captopril. C57BL/6 mice were purchased from The Jackson Laboratories (Bar Harbor, ME). Glomerulonephritis (GN) was induced by intraperitoneal (i.p.) injection of 10 mg of apoferritin from horse spleen (HSA, Sigma, St. Louis, MO) five days per week, with i.p. injection of 100 micrograms lipopolysaccharide (LPS, from Salmonella minnesota; EMD Biosciences, La Jolla, CA), as adjuvant, three times per week. Control animals received equal volumes of 0.15 M NaCl by i.p. injection. Injections were begun when the mice were approximately eight weeks of age and were continued for six weeks. Captopril, at 100 mg/kg/day was given in the drinking water. After 9 weeks, the animals were euthanized and kidneys were removed for RNA purification and analysis.

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

Publications

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

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