RENAL TUBULAR HYPERPLASIA, POLYCYSTIC DISEASE, AND GLOMERULOSCLEROSISIN TRANSGENIC MICE OVEREXPRESSING HEPATOCYTE GROWTH-FACTOR SCATTER FACTOR

Hepatocyte growth factor/scatter factor (HGF/SF) has been implicated a s a renotrophic agent, capable of stimulating renal regeneration after unilateral nephrectomy or acute kidney failure. However, evaluation o f 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 t ubular cystic disease and progressive glomerulosclerosis, and were sus ceptible to premature death from renal failure. The tubular phenotype appeared to result from HGF/SF-Met autocrine stimulation of the tubula r epithelium and consequent hyperplasia. Electron microscopic examinat ion of glomeruli, which also showed enhanced cellular proliferation, r evealed ultrastructural features consistent with focal segmental glome rulosclerosis: an increase in mesangial matrix, effacement of foot pro cesses, and thickening of basement membrane. These changes were not pr esent at birth but developed progressively with age, which is consiste nt with the notion that HGF/SF may not be essential for the early stag es of nephrogenesis, but may play an important role in renal epithelia l renewal and regeneration. Thus, HGF/SF transgenic mice could be a us eful model for dissecting the molecular mechanisms leading to polycyst ic disease and focal segmental glomerulosclerosis. Moreover, our resul ts suggest that caution should be used when considering HGF/SF as a fu ture therapeutic agent.