Role of angiotensin AT2 receptors in natriuresis: Intrarenal mechanisms and therapeutic potential

1. 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 AT(1) and AT(2) receptors. The AT(1) receptors engender antinatriuresis and raise BP, whereas AT(2) receptors oppose these effects, inducing natriuresis and reducing BP. 2. There is high AT(2) receptor expression in the adult kidney, especially in the proximal tubule. In AT(2) receptor-null mice, long-term AngII infusion results in pressor and antinatriuretic hypersensivivity compared with responses in wild-type mice. 3. The major endogenous receptor ligand for AT(2) receptor-mediated natriuretic responses appears to be desaspartyl(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. 4. The renal dopaminergic system is another important natriuretic pathway. Renal proximal tubule the D-1 and D-5 receptor subtypes (D-1-like receptors (D1LIKER)) control approximately 50% of basal sodium excretion. Recently, we have found that natriuresis induced by proximal tubule D1LIKER requires AT(2) receptor activation and that D1LIKER stimulation induces recruitment of AT(2) receptors to the apical plasma membrane via a cAMP-dependent mechanism. 5. Initial studies using the potent AT(2) receptor non-peptide agonist Compound 21 demonstrate natriuresis in both the presence and absence of AT(1) receptor blockade, indicating the therapeutic potential of this compound in fluid-retaining states and hypertension.