Third Department of Internal Medicine, Nara Medical University, Nara, Japan.
Hepatol Res. 2013 Jul;43(7):765-74. doi: 10.1111/hepr.12008. Epub 2012 Nov 20.
Both angiotensin-II (AT-II) and aldosterone (Ald) play pivotal roles in the pathogenesis of diseases in several organs including the liver. We previously reported that suppression of AT-II and Ald with angiotensin-converting enzyme inhibitor (ACE-I) and selective Ald blocker (SAB), respectively, attenuated the rat liver fibrogenesis and hepatocarcinogenesis. The aim of our current study was to elucidate the combined effects of ACE-I and SAB in the progression of a non-diabetic rat model of steatohepatitis, and the possible mechanisms involved.
In the choline-deficient L-amino acid-defined (CDAA) diet-induced model, the effects of ACE-I and SAB on liver fibrosis development and hepatocarcinogenesis were elucidated, especially in conjunction with neovascularization.
Treatment with both ACE-I and SAB suppressed the development of liver fibrosis and glutathione-S-transferase placental form (GST-P) positive pre-neoplastic lesions. The combined treatment with both agents exerted more inhibitory effects as compared with either a single agent along with suppression of the activated hepatic stellate cells (Ac-HSC) and neovascularization, both of which play important roles in these processes. Our in vitro study showed that AT-II type 1 receptor blocker (ARB) and SAB inhibited Ac-HSC proliferation and in vitro angiogenesis along with suppression of the in vivo studies.
Dual blockade of AT-II and Ald suppresses the progression of a non-diabetic rat model of steatohepatitis. Because both agents are widely and safely used in clinical practice, this combination therapy could be an effective new strategy against steatohepatitis in the future.
血管紧张素-II（AT-II）和醛固酮（Ald）在包括肝脏在内的多个器官的疾病发病机制中发挥关键作用。我们之前的报告表明，血管紧张素转换酶抑制剂（ACE-I）和选择性 Ald 阻滞剂（SAB）分别抑制 AT-II 和 Ald，可减轻大鼠肝纤维化和肝癌的发生。我们目前研究的目的是阐明 ACE-I 和 SAB 在非糖尿病大鼠脂肪性肝炎模型进展中的联合作用及其可能涉及的机制。
在胆碱缺乏 L-氨基酸定义（CDAA）饮食诱导的模型中，阐明 ACE-I 和 SAB 对肝纤维化发展和肝癌发生的影响，特别是与新生血管形成的关系。
联合使用 ACE-I 和 SAB 可抑制肝纤维化和谷胱甘肽-S-转移酶胎盘形式（GST-P）阳性前肿瘤病变的发展。与单独使用一种药物相比，联合使用两种药物具有更强的抑制作用，同时抑制激活的肝星状细胞（Ac-HSC）和新生血管形成，这两者在这些过程中都起着重要作用。我们的体外研究表明，AT-II 型 1 受体阻滞剂（ARB）和 SAB 抑制 Ac-HSC 增殖和体外血管生成，同时抑制体内研究。
AT-II 和 Ald 的双重阻断可抑制非糖尿病大鼠脂肪性肝炎模型的进展。由于这两种药物在临床实践中广泛且安全地使用，这种联合治疗可能是未来治疗脂肪性肝炎的一种有效新策略。
