Renal Angiotensin II Type-2 Receptors Are Upregulated and Mediate the Candesartan-Induced Natriuresis/Diuresis in Obese Zucker Rats

Abstract

Recently, there has been a growing interest in studying the role of angiotensin II type-2 (AT 2 ) receptor in renal/cardiovascular function in pathological conditions. The present study was designed to determine the functional role of the AT 2 receptors on natriuresis/diuresis and compare the level of the tubular AT 2 receptor expression in obese and lean Zucker rats (12 weeks old). Under anesthesia, candesartan (angiotensin II type 1 [AT 1 ]–specific antagonist; 100 μg/kg bolus) produced natriuresis/diuresis to a greater degree in obese than in lean rats. The specific AT 2 antagonist PD123319 (50 μg/kg per minute) after candesartan administration abolished the natriuretic/diuretic effects of candesartan in obese rats but not in lean rats. Infusion of AT 2 receptor agonist, CGP-42112A (1 μg/kg per minute), produced greater increase in sodium and urine excretion over basal in obese than in lean rats. The presence of the AT 2 receptor expression in the brush-border and basolateral membranes was confirmed by Western blotting using specific antibody and antigen-blocking peptide. Densitometric analysis of the bands revealed ≈1.5- to 2.0-fold increase in the AT 2 receptor proteins in both membranes of obese compared with lean rats. Our results suggest upregulation of the AT 2 receptors, which play a role in mediating the natriuretic/diuretic effects of AT 1 receptor blockers in obese Zucker rats. We speculate that AT 2 receptors, by promoting sodium excretion, may protect obese Zucker rats against blood pressure increase associated with sodium and water retention.