Abstract 033: Identification of s Primary Renal AT 2 Receptor Defect in Spontaneously Hypertensive Rats (SHR)

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2018-09, Vol.72 (Suppl_1)
• Main Authors: Howell, Nancy L, Kemp, Brandon A, Keller, Susanna R, Gildea, John J, Shao, Weijian, Navar, L. G, Carey, Robert M
• Format: Article
• Language: English
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/hyp.72.suppl_1.033

Abstract only Angiotensin III (Ang III) [des-aspartyl 1 -Ang II] is the predominant endogenous agonist for angiotensin type-2 receptor (AT 2 R)-induced natriuresis in rats. Hypertensive 12 wk-old SHR lack natriuretic responses to Ang III, and renal interstitial (RI) Ang III administration induces natriuresis in 4 wk-old Wistar-Kyoto rats (WKY), but not in 4 wk-old pre-hypertensive SHR. The defect in natriuresis could be explained by the concurrent observation that in WKY, but not SHR, Ang III induced AT 2 R translocation to renal proximal tubule apical plasma membranes and internalization/inactivation of Na + -transporters Na + - H + exchanger-3 (NHE-3) and Na + /K + ATPase (NKA). These findings suggest an Ang III/AT 2 R signaling defect in pre-hypertensive SHR. The present study sought to determine the cause of the defect: (1) accelerated intrarenal Ang III metabolism or (2) a primary AT 2 R (or post-receptor) signaling defect. Selective AT 2 R agonist Compound-21 (C-21) was infused interstitially [20, 40 and 60 ng/kg/min, each dose for 30 min] into experimental (left) kidneys of 4 wk-old WKY and SHR (N=7) pretreated for 24h with systemic infusion of Ang type-1 receptor (AT 1 R) antagonist candesartan (0.01 mg/kg/min by osmotic minipump); vehicle was infused into control (right) kidneys. Pre-infusion urinary Na + excretion (U Na V) was 0.022 ± 0.004 μmol/min in WKY and 0.024 ± 0.005 μmol/min in SHR (P=NS). In WKY, C-21 dose-dependently increased U Na V from 0.022 ± 0.004 to 0.058 ± 0.017, 0.078 ± 0.014 and 0.079 ± 0.079 μmol/min (P=0.01 from pre-infusion and time control kidneys). In contrast, SHR did not increase U Na V in response to C-21 [highest U Na V 0.033 ± 0.007 μmol/min (P=NS from pre-infusion and time control kidneys)]. Mean arterial pressure (MAP) was 64.6 ± 1.80 mmHg in WKY and 76.4 ± 2.2 mmHg (P