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Division of Cellular and Molecular Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261
Hepatocyte growth factor
(HGF) is a renotropic protein that elicits antifibrogenic activity by
preventing the activation of matrix-producing myofibroblast cells in
animal models of chronic renal diseases. However, whether a delayed
administration of HGF can still attenuate renal fibrosis remains
uncertain. In this study, we examined the therapeutic potential of
exogenous HGF on an established renal interstitial fibrosis induced by
unilateral ureteral obstruction (UUO). Three days after UUO, the
obstructed kidneys displayed interstitial fibrotic lesions with
characteristic features of an established renal fibrosis, as manifested
by myofibroblast activation, fibronectin overexpression, interstitial
matrix deposition, and transforming growth factor-
1 upregulation.
Beginning at this time point, administration of recombinant HGF into
mice by intravenous injections for 11 days markedly suppressed the
progression of renal interstitial fibrosis. HGF significantly
suppressed renal 
-smooth muscle actin expression, total kidney
collagen contents, interstitial matrix components, such as fibronectin,
and renal expression of transforming growth factor-1 and its type I
receptor. Compared with the starting point (3 days after UUO), HGF
treatment largely blunted the progression of myofibroblast accumulation and collagen deposition but did not reverse it. Delayed administration of HGF also suppressed the myofibroblastic transdifferentiation from
tubular epithelial cells in vitro, as demonstrated by a decline in
-smooth muscle actin and fibronectin expression. These results suggest that exogenous HGF exhibits potent therapeutic effects on
retarding the progression of an established renal fibrosis.
c-met; renal fibrosis; ureteral obstruction; -smooth muscle
actin; myofibroblast
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