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Cited by 2,453Renin-Angiotensin System StudiesRespiratory Support and MechanismsCoagulation, Bradykinin, Polyphosphates, and Angioedema

Angiotensin-converting enzyme 2 protects from severe acute lung failure

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Imai, Yumiko, Kuba, Keiji, Rao, Shuan, Huan, Yi, Guo, Feng, Guan, Bin, Yang, Peng, Sarao, Renu +10 more·2005·Nature
DOI 10.1038/nature03712PMC PMC7094998
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Abstract

Acute respiratory distress syndrome (ARDS), the most severe form of acute lung injury, is a devastating clinical syndrome with a high mortality rate (30-60%) (refs 1-3). Predisposing factors for ARDS are diverse and include sepsis, aspiration, pneumonias and infections with the severe acute respiratory syndrome (SARS) coronavirus. At present, there are no effective drugs for improving the clinical outcome of ARDS. Angiotensin-converting enzyme (ACE) and ACE2 are homologues with different key functions in the renin-angiotensin system. ACE cleaves angiotensin I to generate angiotensin II, whereas ACE2 inactivates angiotensin II and is a negative regulator of the system. ACE2 has also recently been identified as a potential SARS virus receptor and is expressed in lungs. Here we report that ACE2 and the angiotensin II type 2 receptor (AT2) protect mice from severe acute lung injury induced by acid aspiration or sepsis. However, other components of the renin-angiotensin system, including ACE, angiotensin II and the angiotensin II type 1a receptor (AT1a), promote disease pathogenesis, induce lung oedemas and impair lung function. We show that mice deficient for Ace show markedly improved disease, and also that recombinant ACE2 can protect mice from severe acute lung injury. Our data identify a critical function for ACE2 in acute lung injury, pointing to a possible therapy for a syndrome affecting millions of people worldwide every year.

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  • The AngII-AT1R signaling system plays an important role not only in pneumonia but also in ARDS model mice.

    “The AngII–AT1R signaling system plays an important role not only in pneumonia but also in ARDS model mice (345), indicating that lung injury itself activates the AngII–AT1R signaling.”

    From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [345]

    The Main section reports that AngII acting through the AT1a receptor has a causative role in acute lung failure in mice, supporting the ARDS-model portion of the claim. The Methods describe acid-aspiration, sepsis and endotoxin models; although the Main section names pneumonia as a condition whose lung pathology these models may mimic, it does not separately demonstrate an AngII–AT1R role in pneumonia. Our copy provides no page numbers for these passages. (LLM, conf=0.85)

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  • Lung injury itself activates the AngII-AT1R signaling.

    “The AngII–AT1R signaling system plays an important role not only in pneumonia but also in ARDS model mice (345), indicating that lung injury itself activates the AngII–AT1R signaling.”

    From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [345]

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Authors
Imai, Y., Kuba, K., Rao, S., Huan, Y., Guo, F., Guan, B., Yang, P., Sarao, R., Wada, T., Leong-Poi, H., Crackower, M. A., Fukamizu, A., Hui, C.-C., Hein, L., Uhlig, S., Slutsky, A. S., Jiang, C., & Penninger, J. M.
Affiliations
  • Institute of Molecular Biotechnology (AT)
  • Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
  • St. Michael's Hospital (CA)
  • University of Tsukuba (JP)
  • University of Toronto (CA)
  • University of Freiburg (DE)
  • Research Center Borstel - Leibniz Lung Center (DE)
Corresponding author
Penninger, Josef M.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2005-07-07
Volume
436
Issue
7047
Pages
112-116
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature03712
PMC
PMC7094998
OpenAlex
W1964982019
Cited by
2,453
References
2
Citations by year
2026: 27 · 2025: 45 · 2024: 82 · 2023: 157 · 2022: 253 · 2021: 515 · 2020: 926 · 2019: 22 · 2018: 22 · 2017: 19 · 2016: 23 · 2015: 30 · 2014: 45 · 2013: 33 · 2012: 25
FWCI
29.24
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
Funders
  • Deutsche Forschungsgemeinschaft
  • Österreichischen Akademie der Wissenschaften
  • Oesterreichische Nationalbank
  • Canadian Institutes of Health Research
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Respiratory Support and Mechanisms
  • Health Sciences › Medicine › Genetics › Coagulation, Bradykinin, Polyphosphates, and Angioedema
Keywords
angiotensin-converting enzyme 2, acute respiratory distress syndrome, acute lung injury, renin-angiotensin system, angiotensin II type 2 receptor, angiotensin II type 1a receptor, angiotensin-converting enzyme, acid aspiration, sepsis, pulmonary edema, lung protection
MeSH terms
Angiotensin-Converting Enzyme 2, Acids, Acute Disease, Analysis of Variance, Angiotensin II, Animals, Capillary Permeability, Carboxypeptidases, Disease Models, Animal, Humans, Peptidyl-Dipeptidase A, Lung, Lung Diseases, Mice, Transgenic, Oxygen, Pulmonary Edema, Respiratory Distress Syndrome, Gene Deletion, Mice, Knockout, Sepsis, Transgenes, Receptor, Angiotensin, Type 2, Receptor, Angiotensin, Type 1, Mice

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