Angiotensin II regulates liver regeneration via type 1 receptor following partial hepatectomy in mice.
Angiotensin II (Ang II) is an important mediator stimulating liver fibrosis after liver injury. However, it is not known whether Ang II plays a role in liver regeneration. Here, we investigate the effects of Ang II type 1 (AT(1)) receptor blocker (ARB), angiotensin-converting enzyme inhibitor (ACEI), systemic infusion of Ang II, and genetic deficiency of the AT(1a) receptor (AT1a-KO) on the hepatic regenerative response to partial hepatectomy (PH) in mice. Administration of ARB (candesartan cilexetil and losartan) or ACEI (enarapril and lisinopril) enhanced 5-bromo-2'-deoxyuridine (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 AT1a-KO mice than in wild-type mice. The PH-induced increases in hepatic levels of hepatocyte growth factor (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, blockades of the renin-angiotensin system or Ang II infusion produced opposite effects on the PH-induce increases in hepatic transforming growth factor (TGF)-beta 1 mRNA and plasma TGF-beta 1 levels. These studies suggest that Ang II plays a role in the liver regeneration as a suppressor of hepatocyte proliferation via the AT(1) receptor-mediated control of growth factor production.
Yayama
Katsutoshi
K
Laboratory of Cardiovascular Pharmacology, Department of Biopharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan.
Miyagi
Ryoko
R
Sugiyama
Kaori
K
Sugaya
Takeshi
T
Fukamizu
Akiyoshi
A
Okamoto
Hiroshi
H
D000804:Angiotensin II / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000963:Antimetabolites; D015152:Blotting, Northern; D001973:Bromodeoxyuridine; D006498:Hepatectomy; D017228:Hepatocyte Growth Factor / Q000097:blood / Q000378:metabolism; D008115:Liver Regeneration / Q000187:drug effects* / Q000235:genetics; D008297:Male; D051379:Mice; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000502:physiology*; D012084:Renin-Angiotensin System / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000097:blood / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000963:Antimetabolites; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D017228:Hepatocyte Growth Factor; D001973:Bromodeoxyuridine