Ameliorative effect of hepatocyte growth factor on glycerol-induced acute renal failure with acute tubular necrosis.
OBJECTIVE
Hepatocyte growth factor (HGF), a multi-potent growth factor, is known to promote regeneration of damaged renal epithelial cells. Glycerol injection into rats induces severe acute renal failure (ARF) with ischemia and tubular necrosis, a model which shares many features with human ARF or rhabdomyolysis. We investigated the efficacy of HGF in this glycerol-induced ARF rat model.


METHODS
ARF was induced by intramuscular injection of glycerol into the hind limbs of male Wistar rats. HGF (0.25 mg/kg/shot) or vehicle was administered intravenously 1 h before and 1, 3, 5, 8, 24 and 36 h after glycerol injection. Biochemical parameters for serum and urine were measured and histological analyses of the kidneys were performed. We also analyzed endogenous HGF expression and phosphorylation of c-Met/HGF receptor in the kidneys of glycerol-induced ARF rats.


RESULTS
Glycerol treatment caused severe ARF which invariably led to death of the rats. Repeated administration of HGF protected rats from death caused by severe ARF. Histological analyses revealed that HGF treatment reduced necrosis of tubular cells in the renal cortex. Serum/urine biochemical parameters also showed that renal dysfunction was improved by HGF administration. Intravenous administration of HGF enhanced phosphorylation of the c-Met/HGF receptor and mitogen-activated protein kinase in the kidney. In the vehicle-treated group the renal endogenous HGF concentration decreased and there was no change in c-Met/HGF receptor phosphorylation.


CONCLUSIONS
These results indicate that HGF effectively accelerated the recovery of renal function and improved survival in glycerol-induced ARF rats.
Discovery Research Laboratories II, Sumitomo Pharmaceuticals Research Center, Osaka, Japan.
Tomokazu
T
Nagano
Ikue
I
Mori-Kudo
Atsuchi
A
Tsuchida
Takao
T
Kawamura
Mutsuo
M
Taiji
Hiroshi
H
Noguchi
D000208:Acute Disease; D000818:Animals; D005990:Glycerol / Q000633:toxicity*; D017228:Hepatocyte Growth Factor / Q000627:therapeutic use*; D007684:Kidney Tubules / Q000473:pathology*; D008297:Male; D009336:Necrosis; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000627:therapeutic use; D051437:Renal Insufficiency / Q000139:chemically induced / Q000188:drug therapy*
D011994:Recombinant Proteins; D017228:Hepatocyte Growth Factor; D005990:Glycerol