title: AT1 receptor blockade delays postlactational mammary gland involution: a novel role for the renin angiotensin system.
abstract: Angiotensin II (AngII), the main effector peptide of the renin-angiotensin system (RAS), participates in multiple biological processes, including cell growth, apoptosis, and tissue remodeling. Since AngII activates, in different cell types, signal transducing pathways that are critical for mammary gland postlactational regression, we investigated the role of the RAS during this process. We found that exogenous administration of AngII in mammary glands of lactating Balb/c mice induced epithelium apoptosis [2.9±0.5% (control) vs. 9.6±1.1% (AngII); P < 0.001] and activation of the proapoptotic factor STAT3, an effect inhibited by irbesartan, an AT(1) receptor blocker. Subsequently, we studied the expression kinetics of RAS components during involution. We found that angiotensin-converting enzyme (ACE) mRNA expression peaked 6 h after weaning (5.7-fold; P<0.01), while induction of angiotensinogen and AT(1) and AT(2) receptors expression was detected 96 h after weaning (6.2-, 10-, and 6.2-fold increase, respectively; P<0.01). To assess the role of endogenously generated AngII, mice were treated with losartan, an AT(1) receptor blocker, during mammary involution. Mammary glands from losartan-treated mice showed activation of the survival factors AKT and BCL-(XL), significantly lower LIF and TNF-α mRNA expression (P<0.05), reduced apoptosis [12.1±2.1% (control) vs. 4.8±0.7% (losartan); P<0.001] and shedding of epithelial cells, inhibition of MMP-9 activity in a dose-dependent manner (80%; P<0.05; with losartan IC(50) value of 6.9 mg/kg/d] and lower collagen deposition and adipocyte invasion causing a delayed involution compared to vehicle-treated mice. Furthermore, mammary glands of forced weaned AT(1A)- and/or AT(1B)-deficient mice exhibited retarded apoptosis of epithelial cells [6.3±0.95% (WT) vs. 3.3±0.56% (AT(1A)/AT(1B) DKO); P<0.05] with remarkable delayed postlactational regression compared to wild-type animals. Taken together, these results strongly suggest that AngII, via the AT(1) receptor, plays a major role in mouse mammary gland involution identifying a novel role for the RAS. angiotensin system.
authors.affiliation: IFIBYNE-CONICET, Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Nahmod
authors.forename: Thomas
authors.initials: T
authors.lastname: Walther
authors.forename: Nadia
authors.initials: N
authors.lastname: Cambados
authors.forename: Natalia
authors.initials: N
authors.lastname: Fernandez
authors.forename: Roberto
authors.initials: R
authors.lastname: Meiss
authors.forename: Nils
authors.initials: N
authors.lastname: Tappenbeck
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Diego
authors.initials: D
authors.lastname: Raffo
authors.forename: Marina
authors.initials: M
authors.lastname: Simian
authors.forename: Anja
authors.initials: A
authors.lastname: Schwiebs
authors.forename: Roberto G
authors.initials: RG
authors.lastname: Pozner
authors.forename: Juan I
authors.initials: JI
authors.lastname: Fuxman Bass
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Pozzi
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Geffner
authors.forename: Edith C
authors.initials: EC
authors.lastname: Kordon
authors.forename: Carolina
authors.initials: C
authors.lastname: Schere-Levy
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005260:Female; D020287:In Situ Nick-End Labeling; D007774:Lactation; D008321:Mammary Glands, Animal / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D016133:Polymerase Chain Reaction; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects*; D012084:Renin-Angiotensin System; D015398:Signal Transduction
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II