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Enhancement of the Liver Regeneration by Angiotensin II Type 1 Receptor Blocker : Role of Angiotensin II and Bradykinin

血管紧张素 II 1 型受体阻滞剂增强肝脏再生：血管紧张素 II 和缓激肽的作用

基本信息

批准号：
16590130
负责人：
OKAMOTO Hiroshi
金额：
$ 2.05万
依托单位：
Kobe Gakuin University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

项目摘要

Studies have been undertaken to determine roles of the renin-angiotensin and kallikrein-kinin systems in the liver regeneration using rats and mice. The liver regeneration was evaluated by measuring the frequency of 5-bromo-2'-deoxyuridine (BrdU) incorporation into hepatocyte nuclei 48 h after partial hepatectomy (PH). We found in rats that administration of candesartan or losartan (AT_1 receptor antagonists; ARBs), as well as lisinopril (ACE inhibitor), enhanced BrdU incorporation after PH, and the lisinopril-induced enhancement was inhibited in part (40%) by icatibant. PH induced the expression of hepatocyte growth factor (HGF) mRNA in remnant liver, and this PH-induced up-regulation of HGF mRNA was further enhanced not only by lisinopril but also by ARBs. Administration of icatibant inhibited up to 40% of the lisinopril-induced up-regulation of HGF mRNA. We also found in mice that administration of ARBs (candesartan and losartan) or ACE inhibitors (enarapril and lisinopril) enhanced … More BrdU incorporation into hepatocyte nuclei in remnant liver as well as the restoration of liver weight after PH. Systemic infusion of Ang II (100 ng/kg/min) suppressed the PH-induced BrdU incorporation and the restoration of liver weight. In contrast to Ang II infusion, these hepatic responses to PH were significantly greater in mice (AT1a-KO) lacking the AT_〈1a〉 receptor gene than in wild-type mice. The PH-induced increases in hepatic levels of HGF mRNA and plasma HGF concentrations were greater in candesartan- and enarapril-treated mice or in AT1a-KO mice than in vehicle-treated mice or wild-type mice, respectively, whereas they were less in Ang II-infused mice than in vehicle-infused mice. In contrast to HGF, these blockades of the renin-angiotensin system or Ang infusion produced the opposite effects on the PH-induce increases in hepatic levels of transforming growth factor (TGF)-βl mRNA and plasma TGF-β1 levels.These results suggest that the blockade of the renin-angiotensin system by either ACE inhibitor or ARB enhances the hepatic regenerative response to PH, probably through an augmentation of hepatic HGF production. In addition to this mechanism, the activation of B_2 receptors may also be involved in the ACE inhibitor-induced enhancement of hepatic regenerative response in the rat. Thus, Ang II plays a role in the liver regeneration as a suppressor of hepatocyte proliferation via the ATI receptor-mediated control of growth factor production. Less

已经进行了研究，以确定在大鼠和小鼠的肝再生中的作用的肾素-血管紧张素和激肽释放酶-激肽系统。肝部分切除（PH）后48 h通过测定5-溴-2 '-脱氧尿苷（BrdU）掺入肝细胞核的频率来评价肝再生。我们发现，在大鼠中，给予坎地沙坦或氯沙坦（AT_1受体拮抗剂; ARB）以及赖诺普利（ACE抑制剂），可增强PH后BrdU掺入，而赖诺普利诱导的BrdU掺入被艾替班特部分抑制（40%）。PH诱导残肝肝细胞生长因子（HGF）mRNA表达，赖诺普利和ARB均能进一步增强PH诱导的HGF mRNA表达。艾替班特给药可抑制赖诺普利诱导的HGF mRNA上调达40%。我们还发现，在小鼠中给予ARB（坎地沙坦和氯沙坦）或ACE抑制剂（依那普利和赖诺普利）， ...更多信息 BrdU掺入肝细胞核，以及PH后肝重量的恢复。全身灌注Ang II（100 ng/kg/min）抑制PH诱导的BrdU掺入和肝重量的恢复。与血管紧张素II输注相反，这些肝脏对PH的反应在缺乏AT_（1a）1a受体基因的小鼠（AT_（1a）-KO）中比在野生型小鼠中显著更大。在坎地沙坦和依那普利治疗的小鼠或AT 1a-KO小鼠中，PH诱导的肝脏HGF mRNA水平和血浆HGF浓度的增加分别大于溶媒治疗的小鼠或野生型小鼠，而在Ang II输注的小鼠中，它们小于溶媒输注的小鼠。与HGF相反，阻断肾素-血管紧张素系统或血管紧张素灌注对PH诱导的肝转化生长因子（TGF）-β 1 mRNA水平和血浆TGF-β1水平的增加产生相反的作用，这些结果表明，ACE抑制剂或ARB阻断肾素-血管紧张素系统可能通过增加肝HGF的产生而增强对PH的肝再生反应。除此机制外，B_2受体的激活可能也参与了ACE增强大鼠肝再生反应的机制。因此，血管紧张素II通过ATI受体介导的生长因子产生的控制，作为肝细胞增殖的抑制剂在肝再生中发挥作用。少

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hiroshi Okamoto. Angiotensin-converting enzyme inhibitor enhances liver regeneration following partial hepatectomy Involvement of bradykinin B2 and angiotensin AT1 receptors.

冈本宏.

DOI：
发表时间：
2007
期刊：
Biological and Pharmaceutical Bulletin 30(2)
影响因子：
0
作者：
Katsutoshi Yayama;Kaori Sugiyama;Ryoko Miyagi;Hiroshi Okamoto
通讯作者：
Hiroshi Okamoto

Angiotensin-converting enzyme inhibitor enhances liver regeneration following partial hepatectomy : involvement of bradykinin B2 and angiotensin AT1 receptors.

血管紧张素转换酶抑制剂可增强部分肝切除术后的肝脏再生：涉及缓激肽 B2 和血管紧张素 AT1 受体。

DOI：
发表时间：
2007
期刊：
Biol Pharm Bull. 30(3)
影响因子：
0
作者：
Yayama K;Sugiyama K;Miyagi R;Okamoto H.
通讯作者：
Okamoto H.

Angiotensin II regulates liver regeneration via type lreceptor following partial hepatectomy in mice

血管紧张素 II 通过 I 型受体调节小鼠肝部分切除术后的肝再生

DOI：
发表时间：
期刊：
Biological and Pharmaceutical Bulletin (印刷中)
影响因子：
0
作者：
Katsutoshi Yayama;Ryoko Miyagi;Kaori Sugiyama;Takeshi Sugaya;Akiyoshi Fukamizu;Hiroshi Okamoto
通讯作者：
Hiroshi Okamoto

Angiotensin II regulates liver regeneration via type 1 receptor following partial hepatectomy in mice.

血管紧张素 II 在小鼠部分肝切除术后通过 1 型受体调节肝再生。

DOI：
发表时间：
期刊：
Biological and Pharmaceutical Bulletin (In press)
影响因子：
0
作者：
Katsutoshi Yayama;Ryoko Miyagi;Kaori Sugiyama;Takeshi Sugaya;Akiyoshi Fukamizu;Hiroshi Okamoto
通讯作者：
Hiroshi Okamoto

Angiotensin type 2 receptor-mediated phosphorylation of eNOS in the aortas of mice with 2-kidney, 1-clip hypertension