Li Xu, Meng Ying, Yang Xi-Shan, Mi Ling-Fei, Cai Shao-Xi
Department of Emergency, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China.
World J Gastroenterol. 2005 Aug 21;11(31):4807-11. doi: 10.3748/wjg.v11.i31.4807.
Angiotensin II has pro-fibrotic function in the liver. Blockade of the renin-angiotensin-aldosterone-system (RAAS) attenuates hepatic fibrosis. The aim of the present study was to determine the mechanism of angiotensin-converting enzyme inhibitor (ACEI) on the progression of rat hepatic fibrosis.
Forty male Wistar rats were divided into three groups. Model group (Mo): The rats were injected subcutaneously with 40% of CCl(4) 0.25 mL/100 g. Perindopril group (Pe): The rats were injected subcutaneously with 40% of CCl(4). Perindopril, equivalent to 2 mg/(kg.d), was administrated. Control group (Nc): the rats were treated with olive oil only. After 4 and 6 wk, the rats were killed. The liver sections were stained with Masson. The protein expressions of AT1R, TGF-beta1 and PDGF-BB were examined by Western blot. Nuclear factor kappaB (NF-kappaB) DNA binding activity was examined by EMSA (Electrophoretic gel mobility shift assay). Matrix metalloproteinase-2,9 (MMP-2,9) activity was assessed by zymography. Serum laminin (LN) and hyaluronic acid (HA) were measured using radioimmunoassays.
Using Western blot, we clearly provided direct evidence for the expression of AT1R in liver. The expression was up-regulated when fibrogenesis occurred. Perindopril treatment significantly reduced mean fibrosis score, protein levels of AT1R, TGF-beta1 and PDGF-BB, serum levels of HA and LN, and the activity of MMP-2,9. NF-kappaB DNA binding activity markedly increased in model group, perindopril treatment considerably reduced NF-kappaB DNA binding activity.
Perindopril attenuates CCl(4)-induced hepatic fibrogenesis of rat by inhibiting TGF-beta1, PDGF-BB, NF-kappaB and MMP-2,9.
血管紧张素II在肝脏中具有促纤维化作用。阻断肾素-血管紧张素-醛固酮系统（RAAS）可减轻肝纤维化。本研究的目的是确定血管紧张素转换酶抑制剂（ACEI）对大鼠肝纤维化进展的作用机制。
40只雄性Wistar大鼠分为三组。模型组（Mo）：大鼠皮下注射40%四氯化碳0.25 mL/100 g。培哚普利组（Pe）：大鼠皮下注射40%四氯化碳，并给予相当于2 mg/(kg·d)的培哚普利。对照组（Nc）：大鼠仅用橄榄油处理。4周和6周后，处死大鼠。肝脏切片进行Masson染色。通过蛋白质免疫印迹法检测AT1R、转化生长因子-β1（TGF-β1）和血小板衍生生长因子-BB（PDGF-BB）的蛋白表达。通过电泳凝胶迁移率变动分析（EMSA）检测核因子κB（NF-κB）的DNA结合活性。通过酶谱法评估基质金属蛋白酶-2、9（MMP-2、9）的活性。采用放射免疫分析法测定血清层粘连蛋白（LN）和透明质酸（HA）。
通过蛋白质免疫印迹法，我们明确提供了肝脏中AT1R表达的直接证据。在肝纤维化发生时，该表达上调。培哚普利治疗显著降低了平均纤维化评分、AT1R、TGF-β1和PDGF-BB的蛋白水平、血清HA和LN水平以及MMP-2、9的活性。模型组中NF-κB的DNA结合活性显著增加；培哚普利治疗显著降低了NF-κB的DNA结合活性。
培哚普利通过抑制TGF-β1、PDGF-BB、NF-κB和MMP-2、9减轻四氯化碳诱导的大鼠肝纤维化。
