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Clin Exp Pharmacol Physiol. 2013 Aug;40(8):527-34. doi: 10.1111/1440-1681.12059.

Role of angiotensin AT(2) receptors in natriuresis: Intrarenal mechanisms and therapeutic potential.

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  • 1Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA. rmc4c@virginia.edu


The renin-angiotensin system is a coordinated hormonal cascade critical for the regulation of blood pressure (BP) and kidney function. Angiotensin (Ang) II, the major angiotensin effector peptide, binds to two major receptors, namely AT1 and AT2 receptors. The AT1 receptors engender antinatriuresis and raise BP, whereas AT2 receptors oppose these effects, inducing natriuresis and reducing BP. There is high AT2 receptor expression in the adult kidney, especially in the proximal tubule. In AT2 receptor-null mice, long-term AngII infusion results in pressor and antinatriuretic hypersensivivity compared with responses in wild-type mice. The major endogenous receptor ligand for AT2 receptor-mediated natriuretic responses appears to be des-aspartyl(1) -AngII (AngIII) instead of AngII. Recent studies have demonstrated that AngII requires metabolism to AngIII by aminopeptidase A to induce natriuresis and that inhibition of aminopeptidase N increases intrarenal AngIII and augments AngIII-induced natriuresis. The renal dopaminergic system is another important natriuretic pathway. Renal proximal tubule the D1 and D5 receptor subtypes (D1 -like receptors (D1LIKE R)) control approximately 50% of basal sodium excretion. Recently, we have found that natriuresis induced by proximal tubule D1LIKE R requires AT2 receptor activation and that D1LIKE R stimulation induces recruitment of AT2 receptors to the apical plasma membrane via a cAMP-dependent mechanism. Initial studies using the potent AT2 receptor non-peptide agonist Compound 21 demonstrate natriuresis in both the presence and absence of AT1 receptor blockade, indicating the therapeutic potential of this compound in fluid-retaining states and hypertension.

© 2013 The Authors Clinical and Experimental Pharmacology and Physiology © 2013 Wiley Publishing Asia Pty Ltd.


angiotensin; dopamine; dopamine receptors; hypertension; natriuresis; receptors; renin-angiotensin system

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