AT(1) receptor blockade delays postlactational mammary gland involution: a novel role for the renin angiotensin system

作者：Nahmod Karen A; Walther Thomas; Cambados Nadia; Fernandez Natalia; Meiss Roberto; Tappenbeck Nils; Wang Yong; Raffo Diego; Simian Marina; Schwiebs Anja; Pozner Roberto G; Fuxman Bass Juan I; Pozzi Andrea G; Geffner Jorge R; Kordon Edith C; Schere Levy Carolina^*

来源：The FASEB Journal, 2012, 26(5): 1982-1994.

DOI：10.1096/fj.11-191932

• AKT
• angiotensin II
• apoptosis
• metalloproteases
• STAT3

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 %26lt; 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%26lt;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%26lt;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-alpha mRNA expression (P%26lt;0.05), reduced apoptosis [12.1+/-2.1% (control) vs. 4.8+/-0.7% (losartan); P%26lt;0.001] and shedding of epithelial cells, inhibition of MMP-9 activity in a dose-dependent manner (80%; P%26lt;0.05; with losartan IC50 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%26lt;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.-Nahmod, K. A., Walther, T., Cambados, N., Fernandez, N., Meiss, R., Tappenbeck, N., Wang, Y., Raffo, D., Simian, M., Schwiebs, A., Pozner, R. G., Fuxman Bass, J. I., Pozzi, A. G., Geffner, J. R., Kordon, E. C., Schere-Levy, C. AT(1) receptor blockade delays postlactational mammary gland involution: a novel role for the renin angiotensin system. FASEB J. 26, 1982-1994 (2012). www.fasebj.org

• 出版日期2012-5