Department of Urology, Peking University First Hospital, Beijing, China.
Prostate. 2010 Jun 1;70(8):899-905. doi: 10.1002/pros.21124.
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 beta1 (TGF-beta1) expression. We aimed to investigate the mechanism of inhibition of AT1 receptor in prostate epithelium cells and the role of TGF-beta1.
Human prostate epithelium cell lines were treated with different concentrations of ARB (losartan) (0, 0.1, 1, 10, 100, and 1,000 microM) 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-beta1 was determined by enzyme-linked immunosorbent assay.
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-beta1 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-beta1 in cells treated with losartan was higher than that in untreated cells.
The apoptotic effect of blockade of AT1 receptor on human prostatic epithelium cells may be mediated through an autocrine the production of TGF-beta1. Furthermore, this finding may have implications for medication options. Inc.
良性前列腺增生（BPH）和高血压之间的显著相关性表明这两种疾病存在共同的病理生理因素。肾素-血管紧张素系统（RAS）的活性增强已在 BPH 中报道。血管紧张素 II 型 1（AT1）受体是 RAS 的主要介质，拮抗剂 AT1 受体阻滞剂（ARB）可诱导前列腺上皮细胞凋亡并增加转化生长因子β1（TGF-β1）的表达。我们旨在研究 ARB（氯沙坦）抑制前列腺上皮细胞中 AT1 受体的机制以及 TGF-β1 的作用。
用人前列腺上皮细胞系用不同浓度的 ARB（氯沙坦）（0、0.1、1、10、100 和 1000μM）处理 24-72 小时。通过细胞增殖测定分析细胞增殖。免疫细胞化学和免疫细胞荧光研究显示 AT1 受体的位置。通过末端转移酶 TdT 介导的 dUTP-生物素末端标记（TUNEL）和 caspase 3/7 活性测定分析细胞凋亡。通过 JC-1 染色测量线粒体外膜通透性。通过酶联免疫吸附试验测定 TGF-β1 的水平。
免疫组织化学和免疫荧光分析显示 AT1 受体在上皮细胞中表达。与对照培养物相比，用氯沙坦处理 24-72 小时的培养物显示细胞数量呈剂量依赖性显著减少，凋亡增加 65.2%。用抗 TGF-β1 抗体处理可逆转细胞数量减少。TUNEL 染色显示氯沙坦处理的前列腺上皮细胞凋亡增加。Caspase 3/7 激活增加，线粒体膜电位下调。用氯沙坦处理的细胞中 TGF-β1 的表达高于未处理的细胞。
阻断 AT1 受体对人前列腺上皮细胞的凋亡作用可能是通过自分泌产生 TGF-β1 介导的。此外，这一发现可能对药物选择具有重要意义。
