A rat model of focal segmental glomerulosclerosis (FSGS) produced by repeated injections of aminonucleoside (AMN) of puromycin was used to evaluate the relative roles of hemodynamic alterations and AMN-induced glomerular visceral epithelial cell injury in the development of FSGS. Twenty rats received three intraperitoneal injections of AMN on days 1, 21, and 28 and developed significant proteinuria. On day 50, 14 rats (group 1) underwent selective left renal perfusion with AMN and six rats (group 2) received left renal perfusion with saline. At sacrifice on day 70 or 110, group 2 rats had similar values in left and right kidneys for glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and the amount of FSGS (13.1 +/- 5.6% in left and 12.9 +/- 7.8% in right). In contrast, group 1 rats manifested a significantly higher amount of FSGS in right kidneys as compared to left kidneys (3.1 +/- 1.3% in left and 6.3 +/- 2.0% in right, as well as significantly diminished GFR and ERPF in left as compared to right kidneys. A higher degree of FSGS was seen in kidneys with a higher GFR and ERPF. A positive correlation was observed between the mean 24-h protein excretion of the rats and the percentage of FSGS in left and right kidneys (r = 0.66, p less than 0.01).