Abstract
Objective: The present study used a novel mouse model with proximal tubule-specific knockout of AT1a receptors in the kidney, PT-Agtr1a-/-, to test the hypothesis that intratubular angiotensin II (Ang II) and AT1a receptors in the proximal tubules are required for maintaining normal blood pressure and the development of Ang II-induced hypertension. Design and method: To test our hypothesis, eight groups (n = 7–15 per group) of adult male wild-type, global Agtr1a-/-, and PT-Agtr1a-/-, and PT-Nhe3-/- mice were infused with Ang II (1.5 mg/kg/day, i.p.), or overexpressed an intracellular Ang II fusion protein (Ad-sglt2-ECFP/Ang II) in the proximal tubules of the kidney for 2 weeks. Basal blood pressure and the pressor responses, glomerular filtration rate (GFR) and 24 h urinary natriuretic response, and the pressure-natriuresis response were determined. Results: Basal telemetry blood pressure were ∼15 ± 3 mmHg lower in PT-Agtr1a-/- than wild-type mice and ∼13 ± 3 mmHg higher than Agtr1a-/- mice (P < 0.01). Basal glomerular filtration was ∼23.9% higher (P < 0.01), whereas fractional proximal tubule Na+ reabsorption was lower in PT-Agtr1a-/- mice (P < 0.01). Deletion of AT1a receptors in the proximal tubules augmented the pressure-natriuresis response (P < 0.01), and natriuretic responses to salt loading or Ang III infusion (P < 0.01). Ang II induced hypertension in wild-type, PT-Agtr1a-/- and PT-Nhe3-/- mice, but the pressor response was ∼16 ± 2 mmHg lower in PT-Agtr1a-/- and PT-Nhe3-/-mice (P < 0.01). Deletion of AT1a receptors or NHE3 in the proximal tubules attenuated ∼50% of Ang II-induced hypertension in wild-type mice (P < 0.01), but blocked intracellular Ang II fusion protein-induced hypertension in PT-Agtr1a-/- mice (P < 0.01). Conclusions: Taken together, the results of the present study provide new insights into the critical role of intratubular Ang II/AT1 (AT1a)/NHE3 pathways in the proximal tubules in normal blood pressure control and the development of Ang II-induced hypertension.
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