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

Summary 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 . There is high AT 2 receptor expression in the adult kidney, especially in the proximal tubule. In AT 2 receptor‐null mice, long‐term Ang II infusion results in pressor and antinatriuretic hypersensivivity compared with responses in wild‐type mice. The major endogenous receptor ligand for AT 2 receptor‐mediated natriuretic responses appears to be des‐aspartyl 1 ‐Ang II (Ang III ) instead of Ang II . Recent studies have demonstrated that Ang II requires metabolism to Ang III by aminopeptidase A to induce natriuresis and that inhibition of aminopeptidase N increases intrarenal Ang III and augments Ang III ‐induced natriuresis. The renal dopaminergic system is another important natriuretic pathway. Renal proximal tubule the D 1 and D 5 receptor subtypes (D 1 ‐like receptors (D 1LIKE R)) control approximately 50% of basal sodium excretion. Recently, we have found that natriuresis induced by proximal tubule D 1LIKE R requires AT 2 receptor activation and that D 1LIKE R stimulation induces recruitment of AT 2 receptors to the apical plasma membrane via a cAMP ‐dependent mechanism. 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.