The Nagase analbuminemic rat (NAR), a mutant of the Sprague-Dawley (SD) strain, exhibits persistent hypercholesterolemia, thrombocytosis, and enhanced platelet aggregation, abnormalities possibly involved in the genesis of glomerular sclerosis (GS). Previous observations suggest that these rats never develop aging GS. We studied the development of GS in NAR after 5/6 nephrectomy (Nx). Fifteen days after Nx, marked glomerular hypertension was observed in NAR, compared with only mild elevations in SD rats. Glomerular hypertrophy was more marked in SD rats than in NAR. Enalapril normalized glomerular volume and partially reversed glomerular hypertension in NAR without altering platelet function or cholesterol levels. Glomerular endothelial injury and intraluminal fibrin deposition were seen only in NAR. Two months after Nx, severe GS and massive glomerular lipid deposition were seen in NAR, whereas only mild glomerular injury occurred in SD rats. Enalapril attenuated GS and prevented lipid deposition in NAR. Glomerular hypertension may be a key factor in the genesis of GS in this model in association with endothelial injury, intracapillary coagulation, and lipid accumulation.