Transforming growth factor β1 mediates apoptotic activity of angiotensin II type I receptor blocker on prostate epithelium in vitro

BACKGROUND The significant association of benign prostatic hyperplasia (BPH) and hypertension indicates a common pathophysiological factor for both diseases. Hyperactivity of the renin‐angiotensin system (RAS) has been reported in BPH. Angiotensin II type I (AT1) receptor is the principal mediator of the RAS, and the antagonist, AT1 receptor blocker (ARB), can induce apoptosis in prostate epithelium cells and increase transforming growth factor β1 (TGF‐β1) expression. We aimed to investigate the mechanism of inhibition of AT1 receptor in prostate epithelium cells and the role of TGF‐β1. METHODS Human prostate epithelium cell lines were treated with different concentrations of ARB (losartan) (0, 0.1, 1, 10, 100, and 1,000 µM) for 24–72 hr. Cell proliferation was analyzed by cell proliferation assay. The location of AT1 receptor was shown by immunocytohistochemistry and immunocytofluorescence study. Analysis of apoptosis was by use of terminal transferase TdT‐mediated dUTP‐biotin end labeling (TUNEL) and caspase 3/7 activity assay. Mitochondrial outer‐membrane permeabilization was measured by JC‐1 staining. The level of TGF‐β1 was determined by enzyme‐linked immunosorbent assay. RESULTS Immunohistochemistry and immunofluorescence analysis showed AT1 receptor expressed in epithelium cells. Compared to control cultures, cultures treated with losartan for 24–72 hr showed a dose‐dependent significant decrease in cell number, with apoptosis increased by 65.2%. Decreased cell number was reversed on treatment with anti‐TGF‐β1 antibody. TUNEL staining showed increased apoptosis in prostate epithelium cells exposed to losartan. Caspase 3/7 activation was increased and mitochondrial membrane potential was downregulated. Expression of TGF‐β1 in cells treated with losartan was higher than that in untreated cells. CONCLUSIONS The apoptotic effect of blockade of AT1 receptor on human prostatic epithelium cells may be mediated through an autocrine the production of TGF‐β1. Furthermore, this finding may have implications for medication options. Prostate 70: 899–905, 2010. © 2010 Wiley‐Liss, Inc.