Angiotensin Converting enzyme-2 Is Protective but Downregulated in Human and Experimental Lung Fibrosis

Am J Physiol Lung Cell Mol Physiol. 2008 Jul;295(1):L178-85. doi: 10.1152/ajplung.00009.2008. Epub 2008 Apr 25.

Abstract

Earlier work from this laboratory showed that local generation of angiotensin (ANG) II is required for the pathogenesis of experimental pulmonary fibrosis and that ANG peptides are expressed robustly in the lungs of patients with idiopathic pulmonary fibrosis (IPF). Angiotensin converting enzyme-2 (ACE-2) degrades the octapeptide ANG II to form the heptapeptide ANG1-7 and thereby limits ANG II accumulation. On this basis, we hypothesized that ACE-2 would be protective against experimental lung fibrogenesis and might be downregulated in human and experimental lung fibrosis. In lung biopsy specimens from patients with IPF, ACE-2 mRNA and enzyme activity were decreased by 92% (P<0.01) and 74% (P<0.05), respectively. ACE-2 mRNA and activity were also decreased similarly in the lungs of bleomycin-treated rats and C57-BL6 mice. In mice exposed to low doses of bleomycin, lung collagen accumulation was enhanced by intratracheal administration of either ACE-2-specific small interfering RNAs (siRNAs) or the peptide DX(600), a competitive inhibitor of ACE-2 (P<0.05). Administration of either ACE-2 siRNA or DX(600) significantly increased the ANG II content of mouse lung tissue above the level induced by bleomycin alone. Coadministration of the ANG II receptor antagonist saralasin blocked the DX(600)-induced increase in lung collagen. Moreover, purified recombinant human ACE-2, delivered to mice systemically by osmotic minipump, attenuated bleomycin-induced lung collagen accumulation. Together, these data show that ACE-2 mRNA and activity are severely downregulated in both human and experimental lung fibrosis and suggest that ACE-2 protects against lung fibrogenesis by limiting the local accumulation of the profibrotic peptide ANG II.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Angiotensin II / metabolism*
  • Animals
  • Antibiotics, Antineoplastic / toxicity
  • Bleomycin / toxicity
  • Down-Regulation / drug effects
  • Female
  • Fibrillar Collagens / metabolism
  • Gene Expression Regulation, Enzymologic* / drug effects
  • Humans
  • Lung / enzymology*
  • Male
  • Mice
  • Middle Aged
  • Peptidyl-Dipeptidase A / biosynthesis*
  • Peptidyl-Dipeptidase A / pharmacology
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / enzymology*
  • Pulmonary Fibrosis / prevention & control
  • RNA, Messenger / biosynthesis
  • RNA, Small Interfering / pharmacology
  • Rats

Substances

  • Antibiotics, Antineoplastic
  • Fibrillar Collagens
  • RNA, Messenger
  • RNA, Small Interfering
  • Bleomycin
  • Angiotensin II
  • Peptidyl-Dipeptidase A
  • angiotensin converting enzyme 2