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

已有研究确定肾素-血管紧张素系统和激肽释放酶-激动素系统在大鼠和小鼠肝脏再生中的作用。通过检测肝部分切除(PH)后48h肝细胞核内5-溴-2‘-脱氧尿苷(BrdU)掺入频率来评价肝再生情况。我们在大鼠上发现，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)，可使PH后BrdU掺入增加，而ICATBANT可部分抑制赖诺普利引起的这种增强作用(40%)。PH可诱导大鼠残肝肝细胞生长因子(HGF)mRNA表达，赖诺普利和ARBS均可进一步增强PH诱导的HGF mRNA表达。ICATIBANT可抑制赖诺普利诱导的HGF mRNA上调的高达40%。我们还在小鼠身上发现，给予ARB(坎地沙坦和氯沙坦)或血管紧张素转换酶抑制剂(依那普利和赖诺普利)可增强…残肝肝细胞核内BrdU掺入增加，肝组织重量恢复。全身注射血管紧张素II(100 ng/kg/min)可抑制PH诱导的BrdU掺入和肝脏重量的恢复。与Ang II输注相比，缺乏AT_1a>受体基因的小鼠(AT1a-KO)对PH的这些肝脏反应显著高于野生型小鼠。在坎地沙坦和依那普利治疗的小鼠或AT1a-KO小鼠中，PH诱导的肝脏HGF mRNA水平和血浆HGF浓度的增加分别大于赋形剂治疗的小鼠和野生型小鼠，而注射Ang II的小鼠的升高幅度小于注入赋形剂的小鼠。与肝细胞生长因子相反，阻断肾素-血管紧张素系统或血管紧张素-血管紧张素系统对PH诱导的肝组织转化生长因子-β-β-1水平升高有相反作用。除这一机制外，B_2受体的激活也可能参与了ACE抑制剂诱导的大鼠肝再生反应的增强。因此，Ang II通过ATI受体调节生长因子的产生，作为肝细胞增殖的抑制因子，在肝再生中发挥作用。较少

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