Angiotensin II Type-2 Receptor Effects: Author Reply

The authors thank Drs. Maiolino, Naso and Calo for their kind recognition of our study (1). We are delighted to learn of the evidence from the human model of Bartter's and Gietelman's syndromes that AT₂ receptors (AT₂R) are activated via angiotensin signaling. Indeed, in both of these human syndromes there is marked activation of the renin-angiotensin system (RAS) associated with hypotension, to which AT₂Rs may contribute by direct vasodilation and/or natriuresis.

Numerous studies in experimental animals have shown that AT₂Rs oppose the pressor actions of angiotensin II (Ang II) via AT₁ receptors (AT₁Rs) and lower blood pressure, especially in the presence of AT₁R blockade (2-9). Indeed, AT₂R stimulation lowers blood pressure predominantly under circumstances in which the RAS is activated (10-13) by increasing pressure-natriuresis (11,13). It is likely that the depressor and hypotensive effects of AT₂R activation described in experimental animals translate to human diseases such as Bartter's and Gietelman's syndromes, as evidenced by the above-cited work of Drs. Maiolino, Naso and Calo.

Our recent study (1) demonstrates that selective renal AT₂R activation induces natriuresis in experimental animals by inducing proximal tubule sodium transporter internalization and inactivation. The mechanism by which sodium transporters are inhibited was identified as increased AT₂R-induced renal production of bradykinin, nitric oxide and cyclic GMP, similar to the signaling pathway mediating most, if not all, of the described AT₂R functions, including vasodilation (14).

In contrast to the actions of Ang II to internalize and desensitize AT₁Rs, our studies show that AT₂R activation recruits receptors from intracellular compartments to the apical plasma membranes of proximal tubule cells (1). AT₂R recruitment may therefore serve as a reinforcing positive feedback mechanism which sustains natriuresis in response to activation of the RAS, opposing AT₁R-mediated reduction in sodium excretion. Studies to date show that AT₂R recruitment to the apical plasma membrane is requisite to inhibition of proximal tubule sodium reabsorption (1). The mechanism for translocation of AT₂Rs from cytosol to apical membrane in response to AT₂R activation has been identified by our group as likely to be increased renal cyclic AMP production (15).

It is important to point out that the primary/preferred agonist for endogenous AT₂R activation in experimental animals is not Ang II, but des¹-aspartyl-Ang II (Ang III) (16). Ang II seems to work primarily or exclusively after conversion to Ang III by the action of aminopeptidase A (16,17). Whether Ang III acts as an endogenous AT₂R agonist in human disorders, such as the Bartter's and Gietelman's syndromes, awaits further study.

Recent studies have pointed out the importance of the intrarenal RAS as a local tissue system functioning independently from the systemic system in the pathophysiology of diseases such as hypertension. These studies have shown that the intrarenal RAS is important in the regulation of blood pressure and renal function in experimental animals. This concept is highly likely to apply also to humans. Overactivation of the intrarenal RAS leads to increased Ang II levels, which unlike the systemic RAS, can induce auto-amplification of Ang II production (18-22). AT₁R-dependent Ang II cellular internalization and up-regulated renin synthesized in the distal nephron may provide a sufficient source of continuing intrarenal Ang II formation, to maintain vasoconstriction, antinatriuresis and hypertension (20-22). The precise role of the AT₂R as a counter-regulatory receptor in modulating these intrarenal responses is currently unknown and may be an important area of future investigation.

We anticipate that AT₂R activation might be applied to human conditions of sodium retention such as congestive heart failure and/or hypertension. Our observations suggest that chronic systemic administration of Compound 21, a potent, selective non-peptide AT₂R agonist, counteracts sodium retention and lowers blood pressure in the angiotensin II-infusion model of experimental hypertension in rats (1). Since there is no available diuretic for clinical use in humans that effectively reduces sodium reabsorption at the proximal tubule, it is possible that AT₂R activation in that nephron segment would complement actions of available diuretic/natriuretic agents acting in the ascending limb of Henle, distal tubule and/or collecting duct. This exciting possibility awaits further study.