Abstract P409: Defective Renal Ang III and AT2 Receptor Signaling in Pre-hypertensive Spontaneously Hypertensive Rats (SHR)

Abstract

The intrarenal renin-angiotensin (RAS) system controls blood pressure and electrolyte balance. Angiotensin II (Ang II), the principal RAS effector peptide, is metabolized by aminopeptidase A to des-apartyl 1 -Ang II (Ang III). Our previous studies showed that Ang III, not Ang II, is the preferred endogenous agonist for Ang type-2 receptor (AT 2 R)-induced natriuresis in normal rats, and that hypertensive 12-week old SHR lack natriuretic responses to Ang III. The present study tested whether Ang III induced natriuresis in 4 week old pre-hypertensive SHR by activating/translocating intrarenal AT 2 Rs and internalizing the major renal proximal tubule (RPT) sodium transporter NHE-3. Female 4 week old SHR (N=6) and WKY (N=6) rats were studied after 24 h systemic AT 1 R blockade with candesartan. The left kidney received a 30 min renal interstitial (RI) infusion of vehicle followed by cumulative RI infusions of Ang III (3.5, 7.0, 14, and 28 nmol/kg/min; each dose for 30 min). The right kidney received vehicle RI infusions. In 4 week old WKY, RI Ang III increased urine sodium excretion (U Na V) dose dependently from control of 0.04 ± 0.01 to 0.08 ± 0.02 (P<0.05), 0.09 ± 0.02 (P<0.01), 0.07 ± 0.01 (P<0.05), and 0.07 ± 0.01 (P<0.05) μmol/min. In 4 week old pre-hypertensive SHR, RI Ang III failed to induce natriuresis at all doses except 28 nmol/kg/min (0.03 ± 0.01 vs. 0.05 ± 0.01 μmol/min; P<0.05). There was no change in U Na V in right control kidneys of WKY or SHR. Also, Ang III had no effect on mean arterial pressure (MAP) in WKY or SHR. However, MAP was slightly higher, but normotensive, in SHR than WKY. Control and Ang III infused kidneys were processed for confocal microscopy from a separate group of rats. In WKY, RI Ang III induced translocation of AT 2 Rs from subapical to apical membranes of RPT cells [RPTC] (1767 ± 41 vs. 1313 ± 47 RFU; P<0.001). Simultaneously, Ang III induced retraction of NHE-3 from in SHR, intrarenal Ang III failed to induce AT 2 R translocation, NHE-3 retraction, and pSer 552 -NHE-3 upregulation. These results apical to subapical membranes of RPTCs (1703 ± 90 vs. 1388 ± 91 RFU; P<0.05). Consistent with NHE-3 retraction, Ang III increased pSer 552 -NHE-3 (1102 ± 57 vs. 830 ± 66 RFU; P<0.01). In contrast,demonstrate defective Ang III and AT 2 R signaling in pre-hypertensive SHR.