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Renal angiotensin II AT₂ receptors promote natriuresis in streptozotocin-induced diabetic rats

Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, Texas

Submitted 7 May 2005 ; accepted in final form 19 September 2005

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 AT₂ 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_NaV), 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_NaV (µmol/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_NaV 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 (45 kDa) in brush-border (50-fold) and basolateral membranes (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.

kidney; hypertension

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