AT₁receptor 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.

The effect of liquid diet on the parotid gland and the protective role of L-carnitine: immunohistochemical and ultrastructural study

“…Apoptosis is reportedly common in atrophy of exocrine glands. For example, epithelial cell numbers decrease by apoptosis during involution of the lactating mammary glands after weaning [29]. Acinar cells undergo apoptosis in the atrophic pancreas induced by duct obstruction [40], and similar observations were reported in atrophy of parotid glands following duct ligation [11,27].…”

The angiotensin receptor blocker, Losartan, inhibits mammary tumor development and progression to invasive carcinoma

“…The importance of AT 1 R function on mammary gland morphogenesis during normal development and pregnancy has been characterised by Nahmod and colleagues using mice deficient in either, or both, of the two different murine angiotensin receptors (AT 1A or AT 1B ) and with the administration of Irbesartan, an ARB [40]. Of the two angiotensin receptors, AT 1A, the ortholog of human AT 1 R, mediated signaling was important in tissue remodeling during postlactational mammary gland involution.…”

Angiotensin modulates human mammary epithelial cell motility

“…The results reported by the cited authors together with our present study show how the RAS can play different roles depending on the stage of mammary gland development and differentiation. 33 Puddefoot et al demonstrated that treatment of MCF-7 cells with AngII for 48 h caused concentration-dependent reduction in adhesion to fibronectin, laminin and collagen type IV-coated inserts. This significant inhibition of MCF-7 cell adhesion to fibronectin, laminin and collagen type IV by AngII was attenuated by incubation with the AT1-R antagonist losartan.…”