Intrarenal Angiotensin III Infusion Induces Natriuresis and Angiotensin Type 2 Receptor Translocation in Wistar-Kyoto but not in Spontaneously Hypertensive Rats

Abstract

Abstract-In Sprague-Dawley rats, renal angiotensin (Ang) type 2 receptors (AT 2 Rs) mediate natriuresis in response to renal interstitial (RI) D 1 -like receptor stimulation or RI Ang III infusion. After D 1 -like receptor activation, apical membrane (AM) but not total renal proximal tubule cell AT 2 R expression is increased, suggesting that AM AT 2 R translocation may be important for natriuresis. Key Words: sodium Ⅲ natriuresis Ⅲ angiotensin III Ⅲ AT 2 receptor Ⅲ AT 1 receptor Ⅲ translocation T he renin-angiotensin system is a coordinated hormonal cascade of crucial importance in cardiovascular and renal function. In recent years, an emphasis has been placed on delineating the role of the intrarenal renin-angiotensin system in the regulation of blood pressure (BP) 1,2 and sodium (Na ϩ ) balance. [3][4][5] The majority of the effects of the intrarenal reninangiotensin system are mediated by 2 angiotensin receptors, angiotensin (Ang) type 1 (AT 1 R) and Ang II type II (AT 2 R). Renal AT 1 Rs, as a consequence of their antinatriuretic actions, are required for the development of Ang II-dependent hypertension, because the presence of systemic extrarenal AT 1 Rs alone is not sufficient to sustain hypertensive responses to Ang II infusion. 1 Furthermore, AT 1 Rs in renal proximal tubule cells (RPTCs), as opposed to other sites along the nephron, are primarily responsible for this response. 6 In Sprague-Dawley rats, renal AT 2 Rs have been reported to mediate natriuresis in response to renal interstitial (RI) AT 1 R blockade or Ang III infusion. 3 Inhibition of the conversion of Ang II to Ang III in the kidney abolishes natriuresis mediated by renal AT 2 Rs, indicating that Ang III is the preferred agonist of this response. 4 Thus, RPTC AT 1 Rs and AT 2 Rs are major determinants of BP and Na ϩ responses in normal and hypertensive animals.The intrarenaldopaminergic system also plays an important role in the regulation of Na ϩ balance. Dopamine, synthesized by the RPTCs, mediates diuresis and natriuresis via D 1 -like receptor (D 1 R) activation. 7,8 A physiological interaction between the intrarenal renin-angiotensin system and dopaminergic systems has been reported in normal Sprague-Dawley rats. In response to a high-salt diet, RI D 1 R activation with fenoldapam results in natriuresis and diuresis that is abolished by selective pharmacological inhibition of renal AT 2 Rs with PD-123319 (PD). 9 Furthermore, fenoldapam-induced natriuresis is accompanied by an increase in apical plasma membrane (AM) but not total RPTC AT 2 R expression, as quantified by Western blot analysis. 9 Thus, D 1 R-mediated natriuresis depends on functional renal AT 2 Rs, and one of the mechanisms involves RPTC AT 2 R translocation.Spontaneously hypertensive rats (SHRs) develop hypertension as they age and are widely used as a model to study the development and maintenance of human primary (essential) hypertension. 10 Before the onset of hypertension, SHRs

Angiotensin II Type 2 Receptor–Mediated and Nitric Oxide–Dependent Renal Vasodilator Response to Compound 21 Unmasked by Angiotensin-Converting Enzyme Inhibition in Spontaneously Hypertensive Rats In Vivo

“…Padia et al 32 showed an AT 2 R-mediated natriuretic response accompanied by increased AT 2 R expression in the apical membrane but not in total cell membranes of proximal renal tubules in WKY rats but not in SHR. They suggested that intracellular trafficking of AT 2 R determines this natriuretic response and that a defect in proximal renal tubule trafficking machinery predisposes SHR to defective Na + excretion.…”

Biochemical evaluation of the renin-angiotensin system: the good, bad, and absolute?

“…1). Recent studies suggest that the NH 2 -terminal processing of ANG II to ANG-(2-8) or ANG III by aminopeptidase A may yield a peptide selective for brain AT 1 receptors and kidney AT 2 receptors (18,25,68,103,109). Further NH 2 -terminal processing of ANG III to ANG-(3-8) or ANG IV yields another bioactive peptide that interacts with the insulin-regulated aminopeptidase (4).…”

“…In regard to the AT 2 R, Padia et al (103) find that the receptor protein resides primarily in the cytosolic compartment and rapidly inserts into the apical membrane of the proximal tubules following dopaminergic stimulation to facilitate a natriuretic response. Interestingly, translocation of the AT 2 R in spontaneously hypertensive rats was blunted com- pared with normotensive Wistar-Kyoto rats (103). Biotinylation studies combined with an AT 2 R antibody was used to reveal localization of the receptor on the plasma membrane (103).…”

“…Conversely, alternative RAS pathways may mitigate against the activation of the ACE-ANG II-AT 1 R, particularly in response to the pharmacological blockade of this axis (29,43,47,119). Targeting ACE reduces ANG II expression but enhances the ANG-(1-7)-AT 7 /MasR axis that generally opposes the actions of the ANG II-AT 1 R (29,43,44,103,119,120). AT 1 R antagonists may also increase the formation of ANG-(1-7) through ACE2, as well as shunt ANG II to the AT 2 R pathway that shares similar properties to the ANG-(1-7) system (12,25,29,44,47,119).…”

Effects of Angiotensin Metabolites in the Coronary Vascular Bed of the Spontaneously Hypertensive Rat

“…For instance, AT 2 receptors mediate constriction in the renal medulla of 2-kidney, 1-clip rats 15 and in mesenteric arteries of spontaneously hypertensive rats (SHRs), 16 and the AT 2 receptor-induced natriuresis by Ang III no longer occurs in SHRs. 17 Interestingly, blood pressure-lowering in SHRs restored the vasodilatory function of the AT 2 receptor. 18 Chronic treatment of apolipoprotein E knockout mice with Ang IV reversed vascular dysfunction, possibly by enhancing NO bioavailability in an AT 2 and/or Ang II type 4 receptor-dependent manner.…”