Abstract P646: Vascular AT1 Angiotensin Receptors Regulate Sodium Transporter Abundance in Kidney Epithelium

Abstract

Vasoconstriction is a signature physiological action of angiotensin II (AngII) acting via AT1 receptors (AT1R). In order to define the contribution of AT1R in vascular smooth muscle cells (VSMCs) to BP control, we generated mice with cell-specific deletion of AT1AR from VSMCs (SMKOs) using Cre-loxp technology. Baseline BP was reduced by ~7 mmHg and responses to AngII-induced hypertension were significantly blunted by in SMKO mice compared to controls (16 vs. 30 mm Hg change in BP from baseline after 4 wks AngII, P<0.02). Baseline renal blood flow (RBF) was higher, and renal vasoconstriction after Ang II was impaired in SMKOs. Moreover, SMKO mice displayed Na+ sensitivity and exaggerated natriuresis during chronic AngII infusion. To investigate the mechanism of the lower baseline BP and the enhanced natriuresis during AngII infusion (1000ng/kg/min for 5 days), we measured a panel of key Na+ transporters in the kidney by immunoblot. Baseline measurements in SMKO vs. controls detected reductions in NKCC2 in both cortex (0.8±0.03 vs. 1±0.03; P=0.0002) and medulla (0.6±0.02 vs. 1±0.05; P<0.0001); medullary NHE3 was similarly reduced (0.6±0.07 vs. 1±0.07; P=0.002). In controls, AngII infusion was associated with reduced levels of cortical and medullary NHE3 and medullary NKCC, consistent with the pressure-natriuresis response, whereas cortical NKCC, NCC and ENaC were all significantly activated. By contrast, in SMKOs, there was no AngII infusion dependent depression in cortical or medullary NHE3, nor medullary NKCC. However, the extent of increase in activated (cleaved) αENaC was significantly less than controls (cortex: 1.46±0.16 vs. 2.58±0.17, P=0.002; medulla: 1.49±0.09 vs. 2.22±0.31, P=0.01). Yet, 24 hr urinary aldosterone excretion was not different between the groups (18.6±2.7 vs. 15.8±4.5 ng/24hrs). Our studies indicate that the lower baseline BP in SMKO mice is associated with reduced Na+ transporter abundance along the loop of Henle, and that attenuated hypertension and improved natriuresis during AngII infusion are associated with diminished ENaC activation. In conclusion, we suggest that vascular-epithelial cross-talk modulates renal Na+ handling and thereby contributes to control of BP at baseline and during hypertension.