The ICGN mouse strain is a unique model for naturally occurring nephrotic syndrome. In the present study, we examined the onset of the clinical manifestation of nephrotic syndrome and determined the sequence of intraglomerular events associated with progression of nephrotic conditions. Laboratory analysis revealed that homozygous (nep/nep) mice showed urinary albumin excretion during the suckling stage, rapidly leading to hypoalbuminemia accompanied by body growth failure. Renal pathology demonstrated that an initial intraglomerular event in the nephrotic mice was observed 3 weeks after birth in the form of mesangiolytic lesions, characterized by microaneurysm, platelet accumulation and capillary ballooning. In 6-week-old homozygous mice, mesangial sclerosis, characterized by mesangial expansion and glomerular hypertrophy, was observed in a diffuse fashion. Immunohistochemistry revealed that the glomerular cells in the 3-week-old homozygous suckling mice were positive for α-smooth muscle actin, suggesting a phenotypic change in the mesangial cells. Mesangial expansion, confirmed by the over-deposition of type I collagen, was evident until 6 weeks after weaning, while it was of interest that fibrogenic cytokines such as platelet-derived growth factor and transforming growth factor-β were not detected in the sclerotic glomeruli throughout the observations. Furthermore, the nephrotic features were shown to be resistant to steroid therapy with a high dose of prednisolone. Our results suggest that diffuse mesangial sclerosis, a hereditary glomerular disease, may be genetically generated through early myofibroblast formation, which occurs and develops probably independently of up-regulation of these fibrogenic cytokines. In conclusion, the homozygous nephrotic mouse (ICGN strain) is believed to be a good model for investigating not only nephrotic conditions but also cellular and molecular pathogenesis of diffuse mesangial sclerosis in steroid-resistant infantile nephrotic syndrome.