Proximal Tubule-Specific Deletion Of Angiotensin Ii Type 1a Receptors In The Kidney Attenuates Circulating And Intratubular Angiotensin Ii-Induced Hypertension In Pt-Agtr1a(-/-) Mice

The present study used a novel mouse model with proximal tubule-specific knockout of AT(1a) receptors in the kidney, PT-Agtr1a(-/-), to test the hypothesis that intratubular Ang II (angiotensin II) and AT(1a) receptors in the proximal tubules are required for maintaining normal blood pressure and the development of Ang II-induced hypertension. Twenty-six groups (n=6-15 per group) of adult male wild-type, global Agtr1a(-/-), and PT-Agtr1a(-/-) mice were infused with Ang II (1.5 mg/kg per day, IP), or overexpressed an intracellular Ang II fusion protein in the proximal tubules for 2 weeks. Basal telemetry blood pressure were approximate to 15 +/- 3 mm Hg lower in PT-Agtr1a(-/-) than wild-type mice and approximate to 13 +/- 3 mm Hg higher than Agtr1a(-/-) mice (P<0.01). Basal glomerular filtration was approximate to 23.9% higher (P<0.01), whereas fractional proximal tubule Na+ reabsorption was lower in PT-Agtr1a(-/-) mice (P<0.01). Deletion of AT(1a) 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 approximate to 16 +/- 2 mm Hg lower in PT-Agtr1a(-/-) and PT-Nhe3(-/-)mice (P<0.01). Deletion of AT(1a) receptors or NHE3 (Na+/H+ exchanger 3) in the proximal tubules attenuated approximate to 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). Taken together, the results of the present study provide new insights into the critical role of intratubular Ang II/AT(1) (AT(1a))/NHE3 pathways in the proximal tubules in normal blood pressure control and the development of Ang II-induced hypertension.