Hepatocyte growth factor attenuates renal fibrosis through TGF-β1 suppression by apoptosis of myofibroblasts.
OBJECTIVE
The progression of chronic kidney disease (CKD) is characterized by the persistent accumulation of extracellular matrix. Especially, α-SMA-positive myofibroblasts producing large amounts of TGF-β1 are considered to play a key role in interstitial fibrosis. Although hepatocyte growth factor (HGF) improved renal fibrosis in various models, the molecular mechanisms involved are not yet fully understood.


RESULTS
In this study, the molecular mechanisms of the inhibition of fibrosis by HGF was examined using HGF transgenic mice (HGF-Tg) with angiotensin II (Ang II) infusion in 4 weeks models. HGF-Tg mice showed significantly decreased Ang II-induced renal fibrosis and lesser numbers of interstitial myofibroblasts, whereas the antifibrotic effect of HGF was abrogated using HGF-neutralizing antibody. The antifibrotic action in HGF-Tg mice was concordant with a decrease in TGF- β1, collagen type I and IV mRNA expression and an increase in MMP-2 and MMP-9 expression. Furthermore, HGF-Tg mice treated with Ang II showed apoptosis of myofibroblasts. To further investigate the antifibrotic effect of HGF, cultured human mesangial cells were used. HGF induced apoptosis of myofibroblast. Inhibition of the FAK-ERK-MMP signaling cascade by specific inhibitor or siRNA significantly decreased HGF-induced myofibroblast apoptosis.


CONCLUSIONS
The present study demonstrates that the increase in metalloproteinases through FAK-ERK signaling by HGF promotes myofibroblast apoptosis. Activation of metalloproteinases by HGF in the fibrotic kidney might be considered to attenuate the progression of CKD.
Iekushi
Kazuma
K
Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Osoka, Japan.
Taniyama
Yoshiaki
Y
Azuma
Junya
J
Sanada
Fumihiro
F
Kusunoki
Hiroshi
H
Yokoi
Toyohiko
T
Koibuchi
Nobutaka
N
Okayama
Keita
K
Rakugi
Hiromi
H
Morishita
Ryuichi
R
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002478:Cells, Cultured; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D006801:Humans; D007674:Kidney Diseases / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D058628:Myofibroblasts / Q000473:pathology*; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors*
D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1; D017228:Hepatocyte Growth Factor