Role of Renal Aminopeptidases and Angiotensin Type-2 (AT2) Receptors in Sodium Excretion and Hypertension

  • Robert M. Carey
  • Shetal H. Padia
  • John J. Gildea
  • Susanna R. Keller
Conference paper


The renin–angiotensin system (RAS) is a coordinated hormonal cascade of major critical importance to the regulation of sodium (Na+) excretion and blood pressure. Recent studies from our laboratory have provided evidence for a critical role of angiotensin type-2 receptors (AT2Rs) in the control of renal Na+ excretion in response to different stimuli. In the normal rat, natriuretic responses to intrarenal angiotensin type-1 receptor (AT1R) blockade are abolished by concurrent intrarenal AT2R blockade. Surprisingly, angiotensin II (Ang II) is probably not the major effector of AT2R-mediated natriuresis. We have recently demonstrated that, in the presence of systemic AT1R blockade, intrarenal administration of the heptapeptide derivative of Ang II [des-aspartyl1-Ang II] (Ang III) increases renal Na+ excretion. This effect is also abolished with concurrent AT2R inhibition. In contrast, intrarenal Ang II administration in molar equivalent and higher concentrations did not increase urinary Na+ excretion. These observations suggest that renal AT2Rs mediate natriuresis and that Ang III, not Ang II, is the preferred agonist. This conclusion is bolstered by our observation that intrarenal inhibition of aminopeptidase N (APN), the enzyme that metabolizes Ang III to Ang IV, induces a marked augmentation in natriuretic responses to Ang III in the AT1R-blocked rat. In addition, natriuretic responses to intrarenal administration of dopamine (DA) D1-like receptor (D1R) agonist fenoldopam (FEN) are accompanied by recruitment of AT2Rs to the apical plasma membranes of RPT cells, and intrarenal AT2R blockade with PD abolishes FEN-induced natriuresis. Recent studies also have shown that intrarenal Ang III administration translocates AT2Rs to RPT apical plasma membranes and induces natriuresis in normal Wistar Kyoto rats (WKY) but not in 12-week-old spontaneously hypertensive rats (SHR). These studies suggest that defects in AT2R-mediated natriuresis and cellular trafficking may be important in the pathogenesis of hypertension.


Mean Arterial Pressure Renal Proximal Tubule Apical Plasma Membrane Renal Proximal Tubule Cell Natriuretic Response 
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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Robert M. Carey
    • 1
  • Shetal H. Padia
    • 1
  • John J. Gildea
    • 1
  • Susanna R. Keller
    • 1
  1. 1.Departments of Medicine and PathologyUniversity of Virginia Health SystemCharlottesvilleUSA

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