Abstract P041: Proximal Tubule-specific Deletion Of Angiotensin Ii Type 1a Receptors In The Kidney Lowers Basal Blood Pressure And Attenuates Angiotensin Ii-induced Hypertension By Increasing Glomerular Filtration And The Pressure-natriuresis Response

Abstract

The present study tested the hypothesis that intratubular angiotensin II (Ang II) and AT 1a receptors in the proximal tubules of the kidney plays an important role in basal blood pressure control and in the development of Ang II-induced hypertension. Mutant mice with proximal tubule-specific deletion of AT 1a receptors in the kidney, PT- Agtr1a -/- , were generated to test the hypothesis. Eight 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, i.p.). Basal systolic, diastolic, and mean arterial pressures were ~13 ± 3 mmHg lower in PT- Agtr1a -/- than WT mice ( P <0.01). Basal glomerular filtration rate (GFR), as measured using transdermal FITC-sinistrin, was significantly higher in PT- Agtr1a -/- mice (WT: 160.4 ± 7.0 μl/min vs. PT- Agtr1a -/- : 186.0 ± 6.0 μl/min, P <0.05). Basal 24 h urinary Na + excretion (U Na V) was significantly higher in PT- Agtr1a -/- than WT mice ( P <0.01). In response to Ang II infusion, both WT and PT- Agtr1a -/- mice developed hypertension, and the magnitude of the pressor response to Ang II was similar in WT (Δ43 ± 3 mmHg, P <0.01) and PT- Agtr1a -/- mice (Δ39 ± 5 mmHg, P <0.01). However, the absolute blood pressure level was still 16 ± 3 mmHg lower in PT- Agtr1a -/- mice ( P <0.01). Ang II significantly 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, U Na V 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, U Na V 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 AT 1a receptors significantly augmented the pressure-natriuresis response and natriuretic responses to acute saline infusion ( P <0.01) or a 2% high salt diet ( P <0.01). We concluded that deletion of AT 1a receptors selectively in the proximal tubules lowers basal blood pressure and attenuates Ang II-induced hypertension by increasing GFR and promoting the natriuretic response in PT- Agtr1a -/- mice.