PROXIMAL TUBULE-SPECIFIC DELETION OF AT1A RECEPTORS ATTENUATES ANGIOTENSIN II-INDUCED HYPERTENSION BY INCREASING GLOMERULAR FILTRATION AND THE PRESSURE-NATRIURESIS RESPONSE

Abstract

Objective: The present study tested the hypothesis that Ang II and AT1a receptors in the proximal tubules are required for normal blood pressure homeostasis and full development of Ang II-induced hypertension. Design and method: Six groups (n = 7–12 per group) of adult male wild-type (WT) and PT-Agtr1a-/- mice were infused with or without Ang II for 2 weeks (1.5 mg/kg/day, i.p.). Glomerular filtration rate (GFR) was measued using fluorescein-labeled sinistrin, and natriuretic responses were determined under basal conditions and after Ang II infusion. Results: Basal systolic blood pressure were ∼13 ± 3 mmHg lower in PT-Agtr1a-/- than WT mice (P < 0.01). However, basal GFR was higher in PT-Agtr1a-/- mice (WT: 160.4 ± 7.0 μl/min vs. PT-Agtr1a-/-: 186.0 ± 10 μl/min, P < 0.01). Basal 24 h urinary Na+ excretion (UNaV) was higher in PT-Agtr1a-/- than WT mice (P < 0.01). In response to Ang II infusion, both WT and PT-Agtr1a-/- mice developed hypertension with similar pressor response to Ang II in WT (43 ± 3 mmHg, P < 0.01) and PT-Agtr1a-/- mice (39 ± 5 mmHg, P < 0.01). However, systolic blood pressure was still 16 ± 3 mmHg lower in PT-Agtr1a-/- mice (P < 0.01). Ang II decreased GFR to 132.2 ± 7.0 μl/min in WT mice (P < 0.01), and to 129.4 ± 18.6 μl/min in PT-Agtr1a-/- mice (P < 0.01), respectively. In WT mice, UNaV increased from 139.3 ± 22.3 μmol/24 h in the control group to 196.4 ± 29.6 μmol/24 h in the Ang II-infused group (P < 0.01). In PT-Agtr1a-/- mice, UNaV increased from 172.0 ± 10.2 μmol/24 h in the control group to 264.7 ± 35.4 μmol/24 h in the Ang II-infused group (P < 0.01). The pressor response to Ang II was attenuated, while the natriuretic response was augmented by losartan in WT and PT-Agtr1a-/- mice (P < 0.01). Finally, proximal tubule-specific deletion of AT1a receptors significantly augmented the pressure-natriuresis response and natriuretic responses to acute saline infusion (P < 0.01) or a 2% high salt diet for 2 weeks (P < 0.01). Conclusions: The present study supports the hypothesis that Ang II and AT1a receptors in the proximal tubules are required for normal blood pressure homeostasis and the development of Ang II-induced hypertension.