INTRARENAL ANGIOTENSIN III IS THE PREDOMINANT AGONIST FOR PROXIMAL TUBULE AT2 RECEPTORS

In AT1 receptor (AT1R)-blocked rats, renal interstitial (RI) administration of des-aspartyl1-angiotensin II (Ang III), but not angiotensin II (Ang II), induces natriuresis via activation of angiotensin type-2 receptors (AT2R). In the present study, renal function was documented during systemic AT1R blockade with candesartan in Sprague-Dawley rats receiving unilateral RI infusion of Ang III. Ang III increased urine sodium excretion (UNaV), fractional excretion of sodium (FENa), and fractional excretion of lithium (FELi). RI co-infusion of specific AT2R antagonist PD-123319 (PD) abolished Ang III-induced natriuresis. The natriuretic response observed with RI Ang III was not reproducible with RI Ang (1–7) alone or together with angiotensin converting enzyme (ACE) inhibition. Similarly, neither RI Ang II alone nor in the presence of aminopeptidase A (APA) inhibitor to prevent degradation increased UNaV. In the absence of systemic AT1R blockade, Ang III alone did not increase UNaV, but natriuresis was enabled by the co-infusion of aminopeptidase N (APN) inhibitor and subsequently blocked by PD. In AT1R-blocked rats, RI administration of APN inhibitor alone also induced natriuresis that was abolished by PD. Ang III-induced natriuresis was accompanied by increased RI cyclic GMP levels and was abolished by inhibition of soluble guanylyl cyclase. RI and renal tissue Ang III levels increased in response to Ang III infusion and were augmented by APN inhibition. These data demonstrate that endogenous intrarenal Ang III, but not Ang II or Ang (1–7), induces natriuresis via activation of AT2Rs in the proximal tubule via a cyclic GMP-dependent mechanism and suggest APN inhibition as a potential therapeutic target in hypertension.