Renal tubular hyperplasia, polycystic disease, and glomerulosclerosis in transgenic mice overexpressing hepatocyte growth factor/scatter factor.
Hepatocyte growth factor/scatter factor (HGF/SF) has been implicated as a renotrophic agent, capable of stimulating renal regeneration after unilateral nephrectomy or acute kidney failure. However, evaluation of the therapeutic utility of HGF/SF requires thorough analysis of its effects in an appropriate in vivo model system. To this end, the renal structure and function in HGF/SF transgenic mice were examined. Mice overexpressing HGF/SF in the kidney and serum demonstrated prominent tubular cystic disease and progressive glomerulosclerosis, and were susceptible to premature death from renal failure. The tubular phenotype appeared to result from HGF/SF-Met autocrine stimulation of the tubular epithelium and consequent hyperplasia. Electron microscopic examination of glomeruli, which also showed enhanced cellular proliferation, revealed ultrastructural features consistent with focal segmental glomerulosclerosis: an increase in mesangial matrix, effacement of foot processes, and thickening of basement membrane. These changes were not present at birth but developed progressively with age, which is consistent with the notion that HGF/SF may not be essential for the early stages of nephrogenesis, but may play an important role in renal epithelial renewal and regeneration. Thus, HGF/SF transgenic mice could be a useful model for dissecting the molecular mechanisms leading to polycystic disease and focal segmental glomerulosclerosis. Moreover, our results suggest that caution should be used when considering HGF/SF as a future therapeutic agent.
Takayama
H
H
Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4255, USA.
LaRochelle
W J
WJ
Sabnis
S G
SG
Otsuka
T
T
Merlino
G
G
D000818:Animals; D005260:Female; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D006965:Hyperplasia; D007678:Kidney Glomerulus / Q000473:pathology*; D007684:Kidney Tubules / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D007690:Polycystic Kidney Diseases / Q000209:etiology*
D017228:Hepatocyte Growth Factor