Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA.
Hypertension. 2012 Aug;60(2):387-95. doi: 10.1161/HYPERTENSIONAHA.112.191403. Epub 2012 Jun 11.
In angiotensin type 1 receptor-blocked rats, renal interstitial (RI) administration of des-aspartyl(1)-angiotensin II (Ang III) but not angiotensin II induces natriuresis via activation of angiotensin type 2 receptors. In the present study, renal function was documented during systemic angiotensin type 1 receptor blockade with candesartan in Sprague-Dawley rats receiving unilateral RI infusion of Ang III. Ang III increased urine sodium excretion, fractional sodium, and lithium excretion. RI coinfusion of specific angiotensin type 2 receptor antagonist PD-123319 abolished Ang III-induced natriuresis. The natriuretic response observed with RI Ang III was not reproducible with RI angiotensin (1-7) alone or together with angiotensin-converting enzyme inhibition. Similarly, neither RI angiotensin II alone or in the presence of aminopeptidase A inhibitor increased urine sodium excretion. In the absence of systemic angiotensin type 1 receptor blockade, Ang III alone did not increase urine sodium excretion, but natriuresis was enabled by the coinfusion of aminopeptidase N inhibitor and subsequently blocked by PD-123319. In angiotensin type 1 receptor-blocked rats, RI administration of aminopeptidase N inhibitor alone also induced natriuresis that was abolished by PD-123319. Ang III-induced natriuresis was accompanied by increased RI cGMP 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 aminopeptidase N inhibition. These data demonstrate that endogenous intrarenal Ang III but not angiotensin II or angiotensin (1-7) induces natriuresis via activation of angiotensin type 2 receptors in the proximal tubule via a cGMP-dependent mechanism and suggest aminopeptidase N inhibition as a potential therapeutic target in hypertension.
血管紧张素 1 型受体阻断的大鼠，肾间质（RI）给予去天冬氨酸（1）血管紧张素 II（Ang III）而不是血管紧张素 II 诱导钠通过血管紧张素 2 型受体的激活。在本研究中，在接受单侧 RI 输注 Ang III 的 Sprague-Dawley 大鼠中，用坎地沙坦进行全身血管紧张素 1 型受体阻断时记录了肾功能。Ang III 增加尿钠排泄、钠分数和锂排泄。RI 共输注特异性血管紧张素 2 型受体拮抗剂 PD-123319 可消除 Ang III 诱导的钠排泄。RI Ang III 观察到的利尿反应不能通过 RI 血管紧张素（1-7）单独或与血管紧张素转换酶抑制联合重现。同样，单独的 RI 血管紧张素 II 或在氨基肽酶 A 抑制剂存在下，也不会增加尿钠排泄。在没有全身血管紧张素 1 型受体阻断的情况下，Ang III 单独不会增加尿钠排泄，但共输注氨基肽酶 N 抑制剂可使钠排泄，并随后被 PD-123319 阻断。在血管紧张素 1 型受体阻断的大鼠中，RI 给予氨基肽酶 N 抑制剂单独也诱导了利尿作用，该作用被 PD-123319 消除。Ang III 诱导的利尿作用伴随着 RI cGMP 水平的增加，并被可溶性鸟苷酸环化酶抑制所消除。Ang III 输注后，RI 和肾组织 Ang III 水平增加，并被氨基肽酶 N 抑制增强。这些数据表明，内源性肾内 Ang III 而不是 Ang II 或 Ang （1-7）通过 cGMP 依赖性机制激活近端肾小管中的血管紧张素 2 型受体诱导利尿，并提示氨基肽酶 N 抑制作为高血压的潜在治疗靶点。
