title: Local fetal lung renin-angiotensin system as a target to treat congenital diaphragmatic hernia.
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 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.
authors: Life and Health Sciences Research Institute-ICVS, School of Health Sciences, University of Minho, Braga, Portugal.
authors: Cristina
authors: C
authors: Nogueira-Silva
authors: Emanuel
authors: E
authors: Carvalho-Dias
authors: Paulina
authors: P
authors: Piairo
authors: Susana
authors: S
authors: Nunes
authors: Maria J
authors: MJ
authors: Baptista
authors: Rute S
authors: RS
authors: Moura
authors: Jorge
authors: J
authors: Correia-Pinto
mesh_terms: D057912:Angiotensin II Type 2 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use; D000808:Angiotensinogen / Q000378:metabolism; D000818:Animals; D005260:Female; D005333:Fetus / Q000378:metabolism*; D006548:Hernia, Diaphragmatic / Q000188:drug therapy; D065630:Hernias, Diaphragmatic, Congenital; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011247:Pregnancy; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects*
chemical_list: D057912:Angiotensin II Type 2 Receptor Blockers; D007093:Imidazoles; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000808:Angiotensinogen; C073402:PD 123319; D007703:Peptidyl-Dipeptidase A