Angiotensin II induces apoptosis in human and rat alveolar epithelial cells

Recent work from this laboratory demonstrated potent inhibition of apoptosi s in human alveolar epithelial cells (AECs) by the angiotensin-converting e nzyme inhibitor captopril [B. D. Uhal, C. Gidea, R. Bargout, A. Bifero, O. Ibarra-Sunga, ill. Papp, K. Flynn, and G. Filippatos. Am. J. Physiol. 275 ( Lung Cell. Mel. Physiol. 19): L1013-L1017, 1998]. On this basis, we hypothe sized that apoptosis in this cell type might be induced by angiotensin II ( ANG II) through its interaction with the ANG II receptor. Purified ANG II i nduced dose-dependent apoptosis in both the human AEC-derived A549 cell lin e and in primary type II pneumocytes isolated from adult Wistar rats as det ected by nuclear and chromatin morphology, caspase-3 activity, and increase d binding of annexin V. Apoptosis also was induced in primary rat AECs by p urified angiotensinogen. The nonselective ANG II-receptor antagonist sarala sin completely abrogated both ANG II- and angiotensinogen-induced apoptosis at a concentration of 50 mu g/ml. With RT-PCR, both eel types expressed th e ANG II-receptor subtypes 1 and 2 and angiotensin-converting enzyme (ACE). The nonthiol ACE inhibitor lisinopril blocked apoptosis induced by angiote nsinogen, but not apoptosis induced by purified ANG II. These data demonstr ate the presence of a functional ANG II-dependent pathway for apoptosis in human and rat AECs and suggest a role for the ANG II receptor and ACE in th e induction of AEC apoptosis in vivo.