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

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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