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Molecular Medicine

, Volume 18, Issue 2, pp 231–243 | Cite as

Local Fetal Lung Renin-Angiotensin System as a Target to Treat Congenital Diaphragmatic Hernia

  • Cristina Nogueira-Silva
  • Emanuel Carvalho-Dias
  • Paulina Piairo
  • Susana Nunes
  • Maria J. Baptista
  • Rute S. Moura
  • Jorge Correia-Pinto
Research Article

Abstract

Antenatal stimulation of lung growth is a reasonable approach to treat congenital diaphragmatic hernia (CDH), a disease characterized by pulmonary hypoplasia and hypertension. Several evidences from the literature demonstrated a possible involvement of renin-angiotensin system (RAS) during fetal lung development. Thus, the expression pattern of renin, angiotensin-converting enzyme, angiotensinogen, type 1 (AT1) and type 2 (AT2) receptors of angiotensin II (ANGII) was assessed by immunohistochemistry throughout gestation, whereas the function of RAS in the fetal lung was evaluated using fetal rat lung explants. These were morphometrically analyzed and intracellular pathway alterations assessed by Western blot. In nitrofen-induced CDH model, pregnant rats were treated with saline or PD-123319. In pups, lung growth, protein/DNA ratio, radial saccular count, epithelial differentiation and lung maturation, vascular morphometry, right ventricular hypertrophy and overload molecular markers, gasometry and survival time were evaluated. Results demonstrated that all RAS components were constitutively expressed in the lung during gestation and that ANGII had a stimulatory effect on lung branching, mediated by AT1 receptor, through p44/42 and Akt phosphorylation. This stimulatory effect on lung growth was mimicked by AT2-antagonist (PD-123319) treatment. In vivo antenatal PD-123319 treatment increased lung growth, ameliorated indirect parameters of pulmonary hypertension, improved lung function and survival time in nonventilated CDH pups, without maternal or fetal deleterious effects. Therefore, this study demonstrated a local and physiologically active RAS during lung morphogenesis. Moreover, selective inhibition of AT2 receptor is presented as a putative antenatal therapy for CDH.

Notes

Acknowledgments

This project was funded by Fundação para a Ciência e a Tecnologia (PTDC/SAU-OBD/108051/2008) and by Secção de Neonatologia da Sociedade Portuguesa de Pediatria (Grant ZERU 2008). P Piairo was supported by Fundação para a Ciência e a Tecnologia (reference SFRH/BD/33410/2008). RS Moura was supported by Fundação para a Ciência e a Tecnologia (reference SFRH/BPD/15408/2005). PD-123319 was kindly supplied by Medical Division of Pfizer Inc, Groton, Connecticut, USA.

We would like to thank to Luís Martins for histological technical support and help on animal euthanasia and to Nuno M Pires for Weigert staining and vascular morphometric analysis support.

Supplementary material

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Authors and Affiliations

  • Cristina Nogueira-Silva
    • 1
    • 2
    • 3
  • Emanuel Carvalho-Dias
    • 1
    • 2
    • 4
  • Paulina Piairo
    • 1
    • 2
  • Susana Nunes
    • 5
  • Maria J. Baptista
    • 1
    • 2
    • 6
  • Rute S. Moura
    • 1
    • 2
  • Jorge Correia-Pinto
    • 1
    • 2
    • 7
  1. 1.Life and Health Sciences Research Institute (ICVS), School of Health SciencesUniversity of MinhoBragaPortugal
  2. 2.ICVS/3B’sPT Government Associate LaboratoryBragaPortugal
  3. 3.Department of Obstetrics and GynecologyHospital de BragaBragaPortugal
  4. 4.Department of UrologyHospital de São JoãoPortoPortugal
  5. 5.Department of PediatricsHospital de São JoãoPortoPortugal
  6. 6.Department of Pediatric CardiologyHospital de São JoãoPortoPortugal
  7. 7.Department of Pediatric SurgeryHospital de BragaBragaPortugal

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