Angiotensin-converting enzyme 2 protects from severe acute lung failure (original) (raw)

Nature volume 436, pages 112–116 (2005)Cite this article

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 diverse1,3 and include sepsis, aspiration, pneumonias and infections with the severe acute respiratory syndrome (SARS) coronavirus4,5. At present, there are no effective drugs for improving the clinical outcome of ARDS1,2,3. Angiotensin-converting enzyme (ACE) and ACE2 are homologues with different key functions in the renin–angiotensin system6,7,8. 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 lungs9,10. 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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Acknowledgements

We thank M. Chappell, C. Richardson, B. Seed, U. Eriksson, J. Ishida and all members of our laboratory for discussions and reagents. This work is supported by the Institute for Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) and the Jubilaeumsfonds of the Austrian National Bank. This work is in part supported by the Canadian Institutes of Health Research (CIHR) and the Canada Foundation for Innovation (CFI). K.K. is supported by a Marie Curie Fellowship from the EU. C.J. is supported a Beijing Committee of Science and Technology grant and the Natural Science Fundation of China. L.H. is supported by the Deutsche Forschungsgemeinschaft.

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Author notes

  1. Yumiko Imai and Keiji Kuba: *These authors contributed equally to this work

Authors and Affiliations

  1. IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, A-1030, Vienna, Austria
    Yumiko Imai, Keiji Kuba, Renu Sarao, Teiji Wada & Josef M. Penninger
  2. National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, 100005, Beijing, China
    Shuan Rao, Yi Huan, Feng Guo, Bin Guan, Peng Yang & Chengyu Jiang
  3. Department of Cardiology, St. Michael's Hospital, Ontario, M5B 1W8, Toronto, Canada
    Howard Leong-Poi
  4. Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, Quebec, H3R 4P8, Montreal, Canada
    Michael A. Crackower
  5. Center for Tsukuba Advanced Research Alliance, University of Tsukuba, 305-8577, Tsukuba, Japan
    Akiyoshi Fukamizu
  6. Program in Developmental Biology, The Hospital for Sick Children and Department of Molecular and Medical Genetics, University of Toronto, Ontario, MG5 1X8, Toronto, Canada
    Chi-Chung Hui
  7. Department of Pharmacology, University of Freiburg, 79104, Freiburg, Germany
    Lutz Hein
  8. Division of Pulmonary Pharmacology, Research Center Borstel, 23845, Borstel, Germany
    Stefan Uhlig
  9. Department of Medicine and Interdepartmental Division of Critical Care, University of Toronto, St. Michael's Hospital, Ontario, M5B 1W8, Toronto, Canada
    Arthur S. Slutsky

Authors

  1. Yumiko Imai
  2. Keiji Kuba
  3. Shuan Rao
  4. Yi Huan
  5. Feng Guo
  6. Bin Guan
  7. Peng Yang
  8. Renu Sarao
  9. Teiji Wada
  10. Howard Leong-Poi
  11. Michael A. Crackower
  12. Akiyoshi Fukamizu
  13. Chi-Chung Hui
  14. Lutz Hein
  15. Stefan Uhlig
  16. Arthur S. Slutsky
  17. Chengyu Jiang
  18. Josef M. Penninger

Corresponding author

Correspondence toJosef M. Penninger.

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Competing interests

J.M.P. declares personal financial interests.

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Imai, Y., Kuba, K., Rao, S. et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure.Nature 436, 112–116 (2005). https://doi.org/10.1038/nature03712

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Editorial Summary

Drug hope for SARS

The SARS (severe acute respiratory syndrome) epidemic of 2003 caused almost 800 deaths, many of them due to acute respiratory distress syndrome (ARDS) as a complication. There are no effective drugs available for treating ARDS, but new work in mice suggests that ACE2 (angiotensin-converting enzyme 2) might be an option. ACE2 can protect mice from lung injury in an ARDS-like syndrome, whereas other components of the renin–angiotensin system for controlling blood pressure and salt balance actually make the condition worse. ACE2 is expressed in the healthy lung but downregulated by lung injury and it was shown recently (Nature 426, 450–454; 2003) to be a receptor for the SARS coronavirus.