Angiotensin II AT2 receptors have been implicated to play a role in the regulation of renal/cardiovascular functions under pathological conditions. The present study is designed to investigate the function of the AT2 receptors on renal sodium excretion and AT(2) receptor expression in the cortical membranes of streptozotocin (STZ)-induced diabetic rats. The STZ treatment led to a significant weight loss, hyperglycemia, and decrease in plasma insulin levels compared with control rats. STZ-induced diabetic rats had significantly elevated basal urine flow, urinary sodium excretion rate (U(Na)V), urinary fractional sodium excretion, and urinary cGMP compared with control rats. Infusion of PD-123319, an AT2 receptor antagonist, caused a significant decrease in U(Na)V (mumol/min) in STZ-induced diabetic rats (1 +/- 0.09 vs. 0.45 +/- 0.1) but not in control rats (0.35 +/- 0.05 vs. 0.4 +/- 0.07). The decrease in U(Na)V was associated with a significant decrease in urinary cGMP levels (pmol/min) in STZ-induced diabetic rats (21 +/- 2 vs. 10 +/- 0.8) but not in control rats (11.75 +/- 3 vs. 12.6 +/- 2). The infusion of PD-123319 did not alter glomerular filtration rate (STZ: 0.3 +/- 0.02 vs. 0.25 +/- 0.03; control: 1.4 +/- 0.05 vs. 1.5 +/- 0.09 ml/min) or mean arterial pressure (STZ: 82 +/- 3 vs. 79 +/- 3.5; control: 90 +/- 4 vs. 89 +/- 4 mmHg), suggesting a tubular effect of the drug. Western blot analysis using an AT2 receptor antibody revealed a significantly enhanced expression of the AT2 receptor protein ( approximately 45 kDa) in brush-border ( approximately 50-fold) and basolateral membranes ( approximately 80-fold) of STZ-induced diabetic compared with control rats. In conclusion, our data suggest that the tubular AT2 receptors in diabetic rats are profoundly enhanced and possibly via a cGMP pathway promote sodium excretion in this model of diabetes.