Published Online
on December 13, 2004

A more recent version of this article appeared on February 1, 2005

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Submitted on July 1, 2004
Revised on July 22, 2004

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

Amer C. Hakam and Tahir Hussain^*

From the Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Texas.

^* To whom correspondence should be addressed. E-mail: thussain2{at}uh.edu.

Abstract--Recently, there has been a growing interest in studying the role of angiotensin II type-2 (AT₂) receptor in renal/cardiovascular function in pathological conditions. The present study was designed to determine the functional role of the AT₂ receptors on natriuresis/diuresis and compare the level of the tubular AT₂ receptor expression in obese and lean Zucker rats (12 weeks old). Under anesthesia, candesartan (angiotensin II type 1 [AT₁]-specific antagonist; 100 µg/kg bolus) produced natriuresis/diuresis to a greater degree in obese than in lean rats. The specific AT₂ 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 AT₂ 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 AT₂ 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 AT₂ receptor proteins in both membranes of obese compared with lean rats. Our results suggest upregulation of the AT₂ receptors, which play a role in mediating the natriuretic/diuretic effects of AT₁ receptor blockers in obese Zucker rats. We speculate that AT₂ receptors, by promoting sodium excretion, may protect obese Zucker rats against blood pressure increase associated with sodium and water retention.

Key words: angiotensin II receptors • obesity • angiotensin II • kidney • angiotensin I • rats, Zucker

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