Mineralocorticoid receptor antagonist spironolactone prevents pig serum-induced hepatic fibrosis in rats
Mineralocorticoid receptor antagonist spironolactone prevents pig serum-induced hepatic fibrosis in rats
复制标题
DOI：
10.1016/j.trsl.2006.03.007
复制
发表时间：
2006-09-01
影响因子：
7.8
通讯作者：
Ishibashi, Shun
中科院分区：
文献类型：
--
作者：
Fujisawa, Genro;Muto, Shigeaki;Ishibashi, Shun
盐皮质激素受体(MR)拮抗剂螺内酯(SPL)是预防心血管损伤的有效药物。然而，SPL是否以及如何改善大鼠的肝纤维化尚不清楚。以猪血清(PS)0.5m L，每周2次，ip或赋形剂给药12周，分别作为肝纤维化大鼠和对照组。PS组大鼠皮下注射SPL(50 mg/kg/d，sc)12周。比较3组大鼠肝组织中α-平滑肌肌动蛋白(α-SMA)阳性的肝星状细胞(HSCs)、Na/H交换异构体-1(NHE-1)蛋白、肝组织细胞色素P11B2醛固酮合成酶蛋白的免疫组织化学染色及血浆中的醛固酮浓度。单纯PS组大鼠出现肝纤维化，肝星状细胞和肝细胞中α-SMA阳性的HSCs和NHE-1蛋白表达增加，这些都被SPL抑制。单纯给予PS的大鼠肝星状细胞和肝细胞中的CYP11B2蛋白表达增加，SPL不能抑制其表达。给予PS和SPL的大鼠血浆醛固酮浓度显著高于对照组和单独给予PS的大鼠，尽管对照组和单独给予PS的大鼠之间没有差异。PS诱导的肝纤维化与HSC活化和NHE-1蛋白表达一起通过MRS发生，SPL可能通过抑制PS诱导的肝损伤中HSC激活和NHE-1蛋白表达而减轻肝纤维化。损伤肝脏中产生的醛固酮参与了PS诱导的肝纤维化。
Mineralocorticoid receptor (MR) antagonist spironolactone (SPL) is an effective agent for prevention of cardiovascular injury. However, whether and how SPL ameliorates hepatic fibrosis in rats is unknown. Pig serum (PS) (0.5 mL, twice a week, ip) or vehicle-administered rats for 12 weeks were used as rats with hepatic fibrosis or control rats, respectively. Rats given PS were treated with SPL (50 mg/kg/day, sc) for 12 weeks. Hepatic fibrosis, using picro-sirius red staining and determination of hydroxyproline content, immunohistochemistries of alpha-smooth muscle actin (alpha-SMA)-positive hepatic stellate cells (HSCs), Na/H exchange isoform-1 (NHE-1) protein, CYP11B2 aldosterone synthase protein for liver tissues, and plasma aldosterone concentrations were compared among the 3 groups of rats. Rats given PS alone exhibited hepatic fibrosis as well as increases in the number of the alpha-SMA-positive HSCs and NHE-1 protein expression in HSCs and hepatocytes, all of which were suppressed by SPL. Rats given PS alone revealed increased CYP11B2 protein expression in HSCs and hepatocytes, which was not inhibited by SPL. Plasma aldosterone concentrations were significantly greater in rats given PS and SPL than in control rats and rats given PS alone, although they were not different between control rats and rats given PS alone. PS-induced hepatic fibrosis together with HSC activation and NHE-1 protein expression occurs via MRs, and SPL ameliorates hepatic fibrosis presumably via the inhibition of HSC activation and NHE-1 protein expression in PS-induced liver injuries. The aldosterone produced in the injured liver contributes to the PS-induced hepatic fibrosis.