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

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dc.contributor.authorNogueira-Silva, C
dc.contributor.authorCarvalho-Dias, C
dc.contributor.authorPiairo, P
dc.contributor.authorNunes, S
dc.contributor.authorBaptista, MJ
dc.contributor.authorMoura, RS
dc.contributor.authorCorreia-Pinto, J
dc.date.accessioned2012-11-30T15:11:17Z
dc.date.available2012-11-30T15:11:17Z
dc.date.issued2012
dc.description.abstractAntenatal 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 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 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.por
dc.identifier.citationMol Med. 2012;18(1):231-43por
dc.identifier.urihttp://hdl.handle.net/10400.26/2804
dc.language.isoengpor
dc.peerreviewedyespor
dc.relationMolecular Mechanisms of Temporal-Spatial Control of Embryonic Lung Development
dc.subjectFetopor
dc.subjectHérnia Diafragmáticapor
dc.subjectSistema Renina-Angiotensinapor
dc.titleLocal fetal lung renin-angiotensin system as a target to treat congenital diaphragmatic herniapor
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleMolecular Mechanisms of Temporal-Spatial Control of Embryonic Lung Development
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876-PPCDTI/PTDC%2FSAU-OBD%2F108051%2F2008/PT
oaire.fundingStream5876-PPCDTI
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspor
rcaap.typearticlepor
relation.isProjectOfPublication421168df-7413-4a7a-a2aa-4bfb825a4228
relation.isProjectOfPublication.latestForDiscovery421168df-7413-4a7a-a2aa-4bfb825a4228

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