Intrarenal Angiotensin III Is the Predominant Agonist for Proximal Tubule Angiotensin Type 2 Receptors

Abstract

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.

Angiotensin Type 2 Receptor Stimulation Increases Renal Function in Female, but Not Male, Spontaneously Hypertensive Rats

“…This finding is somewhat surprising given that we and others have previously reported significant natriuretic effects of AT 2 R stimulation alone in numerous male rodent models, including normotensive Sprague-Dawley rats, uninephrectomized rats, and obese Zucker rats. 6,[13][14][15] This finding suggests that the lesser renal AT 2 R expression we and others have identified in male versus female SHRs may be responsible for the lack of natriuretic response of male SHRs to C21 in the present study.…”

A Single Initiating Cause of Hypertension; Potential for Primary Prevention

“…The other important component of Pathway, AT2r inhibits Na+ reabsorption in the proximal tubule via mediation of angiotensin III [70]. N-Aspartyl aminopeptidase required to generate angiotensin III may have a mechanism of release in the kidney common with EGF (mechanotransduction) as proposed in a previous section.…”

“…The second heptapeptide, des-aspartyl Ang II (created via an aminopeptidase) Ang (2-8) has been shown to be the predominant agonist for AT2r in mediating the inhibition of sodium reabsorption from the proximal tubule in the kidney [70].…”

Renin-angiotensin system in the kidney: What is new?

“…It has been corroborated that acute intravenous infusion of Ang-(1-7) induces diuresis, natriuresis and renal vasodilatation [50] . Like to Ang-(1-7), there is another heptapeptide derived from Ang Ⅱ having the opposite effect to Ang Ⅱ, namely Ang-(2-8), also known as Ang Ⅲ. Ang Ⅱ can be hydrolyzed by aminopeptidase A, generating Ang Ⅲ [51] ( Figure 1). Heretofore there has been no evidence of a specific receptor for Ang Ⅲ, and Ang Ⅲ normally binds to AT1 with greater affinity than to the AT2 receptor inducing natriuresis on rats [52,53] .…”

“…Heretofore there has been no evidence of a specific receptor for Ang Ⅲ, and Ang Ⅲ normally binds to AT1 with greater affinity than to the AT2 receptor inducing natriuresis on rats [52,53] . Intrarenal Ang Ⅲ induces natriuresis via the AT2 receptor in the proximal tubule by a cGMP-dependent mechanism [51] . Ang Ⅲ can be hydrolyzed by aminopeptidase N generating Ang-(3-8), also called Ang IV, which can be also generated directly from Ang Ⅱ by D-aminopeptidase [20,54] .…”