Regeneration of injured intestinal mucosa is impaired in hepatocyte growth factor activator-deficient mice.
OBJECTIVE
Hepatocyte growth factor activator (HGFA) is a serum proteinase that specifically converts an inactive single-chain form of hepatocyte growth factor (HGF) into an active 2-chain form. HGFA is produced in its precursor form and then activated in injured tissues. To address the precise role of HGFA and to investigate the mechanisms of HGF activation in injured tissues, we generated mice deficient in HGFA.


METHODS
HGFA-deficient mice were generated using targeted gene disruption. The regenerating process of intestinal mucosa damaged by oral administration of dextran sodium sulfate (DSS) or by rectal administration of acetic acid was examined in both HGFA-deficient and control mice. HGF processing activity was analyzed using Western blotting and an HGF activation assay.


RESULTS
Homozygous mutant mice were viable and fertile without obvious abnormalities. When mice were treated with 3% DSS in drinking water for 6 days followed by distilled water without DSS, 72% of HGFA-deficient mice died through day 12 while 75% of control mice survived injury. Similar results were also observed in the acetic acid-induced intestinal injury; the survival rate was 36.6% in HGFA-deficient mice and 84.2% in control mice. In HGFA-deficient mice, the injured mucosa was not sufficiently covered by regenerated epithelium and the activation of HGF was impaired in the injured colon.


CONCLUSIONS
These results indicate that HGFA is required for repair of injured intestinal mucosa but is not essential for normal development during embryogenesis or after birth.
Itoh
Hiroshi
H
Miyazaki Medical College, University of Miyazaki, Miyazaki, Japan.
Naganuma
Seiji
S
Takeda
Naoki
N
Miyata
Shiro
S
Uchinokura
Shunro
S
Fukushima
Tsuyoshi
T
Uchiyama
Shuichiro
S
Tanaka
Hiroyuki
H
Nagaike
Koki
K
Shimomura
Takeshi
T
Miyazawa
Keiji
K
Yamada
Gen
G
Kitamura
Naomi
N
Koono
Masashi
M
Kataoka
Hiroaki
H
D000818:Animals; D001483:Base Sequence; D022202:Chromosomes, Artificial, Bacterial; D003001:Cloning, Molecular; D003092:Colitis / Q000235:genetics / Q000473:pathology; D017931:DNA Primers; D004195:Disease Models, Animal; D007413:Intestinal Mucosa / Q000293:injuries / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D012038:Regeneration / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000172:deficiency* / Q000235:genetics*; D013997:Time Factors
D017931:DNA Primers; C081092:HGF activator; D012697:Serine Endopeptidases