Glomerular overproduction of oxygen radicals in Mpv17 gene-inactivated mice causes podocyte foot process flattening and proteinuria - A model of steroid-resistant nephrosis sensitive to radical scavenger therapy

Focal segmental glomerulosclerosis is a steroid-resistant glomerular diseas e characterized by foot process flattening and heavy proteinuria, A similar disease was found to occur spontaneously in mice in which the Mpv17 gene w as inactivated by retroviral insertion (Mpv17-/- mice). Here evidence is pr ovided that glomerular damage in this murine model is due to overproduction of oxygen radicals and accumulation of lipid peroxidation adducts that wer e found in isolated glomeruli of Mpv17-/- mice, The development of glomerul ar disease in Mpv17-/- mice was inhibited by scavengers of oxygen radicals (dithiomethylurea) and lipid peroxidation (probucol), but not by steroid tr eatment. Although the glomerular polyanion was greatly reduced in proteinur ic Mpv17-/- mice, it was preserved by antioxidative therapy. These results indicate that the glomerular disease in Mpvl7-/- mice qualifies as a model of steroid-resistant focal segmental glomerulosclerosis and that experiment al therapies with scavengers of oxygen radicals and lipid peroxidation effi ciently ameliorate glomerular damage.