RGD Reference Report - Local fetal lung renin-angiotensin system as a target to treat congenital diaphragmatic hernia. - Rat Genome Database

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Local fetal lung renin-angiotensin system as a target to treat congenital diaphragmatic hernia.

Authors: Nogueira-Silva, C  Carvalho-Dias, E  Piairo, P  Nunes, S  Baptista, MJ  Moura, RS  Correia-Pinto, J 
Citation: Nogueira-Silva C, etal., Mol Med. 2012 Mar 27;18(1):231-43. doi: 10.2119/molmed.2011.00210.
RGD ID: 6903875
Pubmed: (View Article at PubMed) PMID:22113494
DOI: Full-text: DOI:10.2119/molmed.2011.00210

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 (AT(1)) and type 2 (AT(2)) receptors of angiotensin II (ANGII) was assessed by immunohisto-chemistry 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 AT(1) receptor, through p44/42 and Akt phosphorylation. This stimulatory effect on lung growth was mimicked by AT(2)-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 AT(2) receptor is presented as a putative antenatal therapy for CDH.

Annotation

Disease Annotations    

Objects Annotated

Genes (Rattus norvegicus)
Agtr2  (angiotensin II receptor, type 2)

Genes (Mus musculus)
Agtr2  (angiotensin II receptor, type 2)

Genes (Homo sapiens)
AGTR2  (angiotensin II receptor type 2)


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