Please use this identifier to cite or link to this item: http://hdl.handle.net/1822/23965

TitleLocal fetal lung renin-angiotensin system as a target to treat congenital diaphragmatic hernia
Author(s)Silva, Cristina Nogueira
Dias, Emanuel Carvalho
Piairo, Paulina C.
Nunes, Susana
Baptista, Maria João Ribeiro Leite
Moura, Rute S.
Pinto, Jorge Correia
Issue dateMar-2012
PublisherFeinstein Institute for Medical Research
JournalMolecular Medicine
Abstract(s)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.
TypeArticle
URIhttp://hdl.handle.net/1822/23965
DOI10.2119/molmed.2011.00210
ISSN1076-1551
Publisher versionhttp://dx.doi.org/10.2119%2Fmolmed.2011.00210
Peer-Reviewedyes
AccessOpen access
Appears in Collections:ICVS - Artigos em Revistas Internacionais com Referee

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