Objective: Mutations in NPHS2 gene, encoding podocyte specific protein podocin, cause hereditary nephrotic syndrome. Knock-in mice carrying the R140Q mutation, murine analogue of the most common human mutation R138Q, show developmental arrest of podocytes and renal failure at neonatal age. The aim of this study was to quantify renal histopathological changes in mice with postnatally induced R140Q hemizygosity. Method: C57BL/6 mice with Nphs2Flox/R140Q, Cre + genotype were injected with Tamoxifen for 5 days to induce hemizygosity for R140Q-mutant podocin. Tissue samples were collected at defined intervals after induction. Renal morphology was evaluated by quantitative histology, immunohistochemistry and electron microscopy. Results: Animals developed proteinuria within 1 week that progressed into renal failure and advanced uremia at week 12-16. The number of podocytes per glomerulus started decreasing at week 2 (42±19 vs. 98±31, p= 0.05), whereas glomerular sclerosis index increased from week 4 (1.5±0.15 vs. 0.25±0.08, p<0.00001). Interstitial changes included fibrosis (up to 20 % of section area in end stage renal disease), tubular atrophy and dilatation. Conclusion: Our results implicate that the expression of mutated podocin in induced R140Q-podocin mice leads to podocyte loss that precedes interstitial damage and glomerulosclerosis. Quantification of histological changes will enable better evaluation of the efficacy of different pharmacological approaches directed to improvement of podocyte viability and attenuation of glomerulosclerosis.