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

• 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
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590130/
• 关键词: Liver; Liver Regeneration; Angiotensin II; Bradykinin; Angiotensin Receptor Blocker; Angiotensin-Converting Enzyme Inhibitor; Angiotensin AT1 Receptor; Bradykinin B2 Receptor; アンジオテンシン; AT1受容体; 肝細胞増殖因子; アンジオテンシン受容体遮断薬; レニンーアンジオテンシン系

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

研究已经开始确定肾素-血管紧张素和钾化钙素-激肽系统在大鼠和小鼠肝脏再生中的作用。肝部分切除（PH）后48 h，通过测定5-溴-2′-脱氧尿苷（BrdU）并入肝细胞核的频率来评估肝再生。我们在大鼠中发现，给予坎地沙坦或氯沙坦（AT_1受体拮抗剂；ARBs）以及赖诺普利（ACE抑制剂），可增强PH后BrdU的结合，赖诺普利诱导的增强被伊卡班特部分（40%）抑制。PH诱导残肝中肝细胞生长因子（HGF） mRNA的表达，赖诺普利和ARBs均能进一步增强PH诱导的HGF mRNA表达。伊卡伐特抑制赖诺普利诱导的HGF mRNA上调高达40%。我们还在小鼠实验中发现，给药ARBs（坎地沙坦和氯沙坦）或ACE抑制剂（依那普利和赖诺普利）可以增强BrdU在残肝中向肝细胞核的掺入以及ph后肝脏重量的恢复。全身输注Ang II （100 ng/kg/min）可以抑制ph诱导的BrdU掺入和肝脏重量的恢复。与angii输注相比，缺乏AT_ < 1a >受体基因的小鼠（AT1a-KO）对PH的这些肝脏反应明显大于野生型小鼠。坎地沙坦和依那普利处理的小鼠或AT1a-KO小鼠中ph诱导的肝脏HGF mRNA水平和血浆HGF浓度的增加分别高于对照处理的小鼠或野生型小鼠，而注入Ang ii的小鼠则低于对照处理的小鼠。与HGF相反，肾素-血管紧张素系统的阻断或Ang输注对ph诱导的肝脏转化生长因子(TGF) -β1 mRNA水平和血浆TGF-β1水平的升高产生相反的作用。这些结果表明，通过ACE抑制剂或ARB阻断肾素-血管紧张素系统，可能通过增加肝脏HGF的产生，增强了肝脏对PH的再生反应。除此之外，B_2受体的激活也可能参与了ACE抑制剂诱导的大鼠肝脏再生反应的增强。因此，Ang II通过ATI受体介导的对生长因子产生的控制，作为肝细胞增殖的抑制因子，在肝再生中发挥作用。少

项目成果

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

冈本宏.

• 发表时间: 2007
• 期刊: Biological and Pharmaceutical Bulletin 30(2)
• 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。

• 发表时间: 2007
• 期刊: Biol Pharm Bull. 30(3)
• 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

• 期刊: Biological and Pharmaceutical Bulletin (印刷中)
• 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。

• 期刊: Biological and Pharmaceutical Bulletin (In press)
• 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

• DOI: 10.1161/01.hyp.0000164571.77710.19
• 发表时间: 2005-05-01
• 期刊: HYPERTENSION
• 影响因子: 8.3
• 作者: Hiyoshi, H;Yayama, K;Okamoto, H
• 通讯作者: Okamoto, H