The present study compared the progression of renal injury in Sprague Dawley (SD) and Dahl salt-sensitive (SS) treated with streptozotocin (STZ). The rats received an injection of STZ (50 mg/kg, i.p.) and an insulin pellet (2 U/day, s.c.) to maintain the blood glucose levels between 400-600 mg/dL. Twelve weeks later, arterial pressure (143±6 vs. 107±8 mmHg) and proteinuria (557±85 vs. 81±6 mg/day) were significantly elevated in STZ-SS rats compared to the values observed in STZ-SD rats, respectively. The kidneys from STZ-SS rats exhibited thickening of glomerular basement membrane, mesangial expansion, severe glomerulosclerosis, and renal interstitial fibrosis occasional glomerular nodule formation. In additional studies, treatment with a therapeutic dose of insulin (4 U/day, s.c.) attenuated the development of proteinuria (212±32 mg/day) and renal injury independent of changes in arterial pressure in STZ-SS rats. Since STZ-SS rats developed severe renal injury, we characterized the time course changes in renal hemodynamics during the progression of renal injury. After 9 weeks of diabetes, there was a 42% increase in GFR in STZ-SS rats versus time-control SS rats with reduced RBF. These results indicate that SS rats treated with STZ develop hyperfiltration and progressive proteinuria and display renal histological lesions characteristic to those seen in patients with diabetic nephropathy. Overall, this model may be useful to study signaling pathways and mechanisms that play role in the progression of diabetes-induced renal disease and the development of new therapies to slow the progression of diabetic nephropathy.