缬沙坦对大鼠急性肝衰竭的保护作用及其机制研究

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摘要目的探讨缬沙坦对大鼠急性肝衰竭的保护作用及其分子机制。方法将60只健康雄性SD大鼠采用随机数字表法分为正常对照组、肝衰竭组、缬沙坦组，每组20只。正常对照组腹腔注射生理盐水，肝衰竭组腹腔注射D-氨基半乳糖（D-GalN）/脂多糖（LPS）造模；缬沙坦组造模前30 min腹腔注射缬沙坦（25 mg/kg）。观察各组大鼠的存活情况，检测大鼠造模10 h后血清和肝脏组织中血管紧张素Ⅱ（AngⅡ）、血管紧张素1-7（Ang 1-7）、AngⅡ/Ang 1-7比值，以及血清中的谷丙转氨酶（ALT）、谷草转氨酶（AST）、肿瘤坏死因子α（TNF-α）、白细胞介素-6（IL-6），观察肝脏组织中炎症坏死水平，并分析葡萄糖调节蛋白78（GRP78）、CCAAT/增强子结合蛋白同源蛋白（CHOP）分子的表达水平。结果缬沙坦组的生存率高于肝衰竭组，差异有高度统计学意义（P ＜ 0.01）。缬沙坦组血清和肝脏组织中的AngⅡ水平、AngⅡ/ Ang 1-7比值均低于肝衰竭组，Ang 1-7水平均高于肝衰竭组，差异有高度统计学意义（均P ＜ 0.01）。缬沙坦组血清的ALT、AST、TNF-α、IL-6水平均低于肝衰竭组，差异有高度统计学意义（均P ＜ 0.01）。肝衰竭组肝脏组织部分肝小叶结构紊乱，肝细胞变性坏死严重，而缬沙坦组肝脏组织肝细胞变性坏死较肝衰竭组减少。缬沙坦组的肝脏组织中GRP78、CHOP的表达水平均低于肝衰竭组，差异有高度统计学意义（均P ＜ 0.01）。结论缬沙坦通过阻断肾素-血管紧张素系统，能够对急性肝衰竭产生保护作用，其作用机制可能与抑制肝脏的内质网应激水平有关。

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	李建州1 刘小静1 叶峰1 李晓青2

关键词 ：急性肝衰竭, 肾素-血管紧张素系统, 内质网应激, 血管紧张素Ⅱ

Abstract：Objective To investigate the protective effect and mechanism of Valsartan on acute liver failure in rats. Methods A total of sixty healthy male SD rats were divided into normal control group, liver failure group, and Valsartan group by random number table method, with 20 rats in each group. Normal control group was intraperitoneally injected with normal saline, liver failure group was intraperitoneally injected with D-galactosamine (D-GalN) / lipopolysaccharide (LPS) for modeling; Valsartan group was intraperitoneally injected with Valsartan (25 mg/kg) 30 min before modeling. The survival of rats in each group was observed. The levels of angiotensinⅡ (AngⅡ) and angiotensin 1-7 (Ang 1-7), and the radio of AngⅡ/Ang 1-7 in serum and liver tissues, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) in serum of rats were detected ten hours after model building. The level of inflammation andnecrosis in liver tissues was observed. The expression levels of glucose regulatory protein 78 (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP) in liver tissues were detected. Results The survival rate in Valsartan group was higher than that in liver failure group, and the difference was highly statistically significant (P ＜ 0.01). The levels of AngⅡ and the radio of AngⅡ/Ang 1-7 in serum and liver tissues in Valsartan group were lower than those in liver failure group, and Ang 1-7 in Valsartan group were higher than that in liver failure group, with high statistical significance (all P ＜ 0.01). Serum levels of ALT, AST, TNF-α and IL-6 in Valsartan group were lower than those in liver failure group, and the differences were highly statistically significant (all P ＜ 0.01). In the liver failure group, the structure of liver lobules of part of liver tissues was disordered and the degeneration and necrosis of liver cells were serious. The degeneration and necrosis of liver cells in Valsartan group was less than that in liver failure group. The expression levels of GRP78 and CHOP in liver tissues of Valsartan group were lower than those of liver failure group, and the differences were highly statistically significant (all P ＜ 0.01). Conclusion Valsartan can significantly reduce liver inflammation and liver cell apoptosis in the process of acute liver failure by blocking renin-angiotensin system, and its protective effect may be related to the inhibition of endoplasmic reticulum stress.

Key words： Acute liver failure Renin-angiotensin system Endoplasmic reticulum stress AngiotensinⅡ

基金资助:国家自然科学基金资助项目（81700559）。

通讯作者: 李晓青（1986.12-），女，硕士；研究方向：肝衰竭与人工肝。

作者简介: 李建州（1986.1-），男，博士；研究方向：肝衰竭与人工肝。

引用本文:

李建州1 刘小静1 叶峰1 李晓青2. 缬沙坦对大鼠急性肝衰竭的保护作用及其机制研究[J]. 中国医药导报, 2021, 18(16): 4-8,29.
LI Jianzhou1 LIU Xiaojing1 YE Feng1 LI Xiaoqing2. Study on the protective effect and mechanism of Valsartan on acute liver failure in rats. 中国医药导报, 2021, 18(16): 4-8,29.

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https://www.yiyaodaobao.com.cn/CN/ 或 https://www.yiyaodaobao.com.cn/CN/Y2021/V18/I16/4

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