Exogenously administered HGF activator augments liver regeneration through the production of biologically active HGF.
Hepatocyte growth factor (HGF) plays a crucial role in the recovery of injured liver. Liver functions are mostly impaired in patients with liver diseases including cirrhosis. However, a significant amount of inactive HGF precursor (proHGF) is reported in the plasma of these patients. proHGF is proteolytically converted to an active form (mature HGF) by HGF-activator. Thus conversion of proHGF into mature HGF presumably contributes to the recovery of liver functions. In this study, rats with a partial hepatectomy were used, as proHGF is accumulated in the remnant liver. Recombinant human HGF-activator was administered via the portal vein to investigate the effect on molecular forms of HGF and its biological signaling. rhHGF-activator promptly converted proHGF into mature HGF, reaching maximal levels at 5-10 min after the injection, while the decreased proHGF was quickly recovered to the initial levels in the liver. The HGF receptor/c-Met was found to be autophosphorylated in the liver treated with rhHGF-activator. Further, the proliferating cell nuclear antigen labeling index and the liver regeneration rate were significantly higher in rhHGF-activator group than in control animals. These results indicate that exogenously administered HGF-activator produces a biologically active HGF from its precursor form and increases the potential for liver regeneration in vivo.
Kaibori
Masaki
M
First Department of Surgery, Kansai Medical University, 10-15 Fumisonocho, Moriguchi, Osaka 570-8506, Japan.
Inoue
Tomohisa
T
Oda
Michio
M
Naka
Daiji
D
Kawaguchi
Toshiya
T
Kitamura
Naomi
N
Miyazawa
Keiji
K
Kwon
A-Hon
AH
Kamiyama
Yasuo
Y
Okumura
Tadayoshi
T
D000818:Animals; D015153:Blotting, Western; D002455:Cell Division; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006498:Hepatectomy; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis* / Q000097:blood; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D011233:Precipitin Tests; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D012038:Regeneration; D012697:Serine Endopeptidases / Q000378:metabolism* / Q000494:pharmacology*; D015398:Signal Transduction; D013997:Time Factors
D018076:DNA, Complementary; D018809:Proliferating Cell Nuclear Antigen; D011994:Recombinant Proteins; D017228:Hepatocyte Growth Factor; C081092:HGF activator; D012697:Serine Endopeptidases