Angiotensin Type-2 Receptors: Transducers of Natriuresis in the Renal Proximal Tubule

Angiotensin II (Ang II) type-2 receptors (AT(2)R) are expressed in the adult kidney, prominently in renal proximal tubule cells (RPTCs), and play an important role in opposing renal sodium (Na(+)) retention induced by Ang II stimulation of Ang II type-1 receptor (AT(1)R). Natriuresis induced by AT(1)R blockade is due at least in part to AT(2)R activation and whole body deletion of AT(2)Rs reduces the natriuretic response to increased blood pressure (BP). The major endogenous AT(2)R agonist mediating the natriuretic response is Ang III, the Ang II heptapeptide metabolite generated by aminopeptidase A, and the principal nephron site mediating inhibition of Na(+) reabsorption by the AT(2)R is the renal proximal tubule (RPT). AT(2)Rs induce natriuresis via a bradykinin, nitric oxide and cyclic GMP (cGMP) signaling cascade. Recent studies demonstrated a key role for protein phosphatase 2A (PP2A) in the AT(2)R-mediated natriuretic response upstream of cGMP. By inducing natriuresis, AT(2)Rs lower BP in the Ang II-infusion model of hypertension. PP2A activation and the natriuretic response to AT(2)R stimulation are defective in spontaneously hypertensive rats, a model of primary hypertension in humans. AT(2)R agonists are candidates for proximal tubule natriuretic agents in Na(+) and fluid retention disorders.