Abnormalities in lipid metabolism resulting from nephrotic syndrome may play a role in the progression of initial glomerular injury to focal and segmental glomerulosclerosis (FSGS). In order to more specifically assess this, we fed male Sprague-Dawley rats, made nephrotic with a single intravenous injection of puromycin aminonucleoside (PA), either normal rodent chow (Group 1) or the same formulation supplemented with 4% cholesterol/1% cholic acid (Group 2). This 4% cholesterol/1% cholic acid-added diet was utilized because, in normal, non-nephrotic rats, this alimentary supplement produces, for the most part, only a significant rise in fasting serum cholesterol and not fasting serum triglycerides. FSGS developed 18 weeks after PA delivery, and both groups of rats were studied functionally and morphologically. Group 2 rats had significantly higher daily urine protein excretion, lower inulin clearance, and greater blood urea nitrogen concentrations than Group 1 animals. Histologically, Group 2 animals demonstrated a significantly greater percentage of glomeruli examined with segmental areas of glomerulosclerosis/hyalinosis, mesangial cell proliferation, and mesangial "foam" cells. At 2, 4, 12, and 18 weeks after PA delivery, the fasting serum cholesterol was always significantly greater in Group 2 rats, whereas in regards to fasting serum triglycerides it was only significantly elevated in Group 2 rats at 4 and 12 weeks after PA administration.