Progressive adriamycin nephropathy in mice: Sequence of histologic and immunohistochemical events

Background. As an experimental analogue of human focal glomerular sclerosis (FGS), adriamycin (ADR)-induced nephropathy is well-characterized in rats. Previously, this model has not been fully established in mice. The extension of this model to the mouse would be useful in the application of genetic and monoclonal antibody technology to characterize mechanisms of progressive renal disease. Herein, we describe a stable and reproducible murine model of chronic proteinuria induced by ADR. Methods. Male BALB/c mice were intravenously injected with a single dose of ADR (10 to 11 mg/kg). Seven mice were sacrificed at weeks 1, 2, 4, and 6. Renal function, quantitative morphometric analysis, and electron microscopic studies were performed. Peripheral CD4(+) and CD8(+) T cells were evaluated using flow cytometric analysis of splenocytes. The leukocytic inflammatory pattern was analyzed by immunohistochemical examination. Results. Overt proteinuria was observed from day 5 and remained significantly elevated throughout the study period. A focal increase in reabsorption droplets in tubular cells appeared at weeks 1 and 2, and numerous intraluminal casts were present after two weeks. Glomerular vacuolation and mild FGS appeared at week 4. At week 6, extensive focal and even global glomerular sclerosis, associated with moderate interstitial expansion and severe inflammation, were observed. A prominent macrophage infiltration appeared within both interstitium and glomeruli at week 2, followed by accumulation of both CD4(+) and CD8(+) T cells in interstitium but not glomeruli. There were almost no B lymphocytes seen at any time. Conclusion. This model should be useful in unraveling the pathogenesis of glomerular and interstitial inflammation and fibrosis in chronic proteinuric renal disease.