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Renal
Tubular Hyperplasia, Polycystic Disease, and Glomerulosclerosis in Transgenic
Mice Overexpressing Hepatocyte Growth Factor/Scatter Factor |
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Hisashi Takayama,
William J. LaRochelle, Sharda G. Sabnis, Toshiyuki Otsuka, and Glenn Merlino
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Laboratories
of Molecular Biology (HT, TO, GM) and Cellular and Molecular Biology (WJL),
National Cancer Institute, National Institutes of Health, Bethesda, Maryland;
and Division of Nephropathology of the Department of Genitourinary Pathology
(SGS), Armed Forces Institute of Pathology, Washington, D.C. |
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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. |
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