Genetic Deletion of AT _1a Receptors Selectively in The Proximal Tubules of The Kidney Attenuates Angiotensin II‐induced Hypertensive and Glomerular Filtration Responses in Aging PT‐ Agtr1a ^‐/‐ Mice

The intratubular renin-angiotensin system (RAS) via the angiotensinogen/renin/ACE/Ang II/AT1 (AT1a) receptor signaling pathways in the proximal tubules of the kidney play a critical role in the physiological regulation of blood pressure and the development of hypertension. Whether intratubular RAS continues to exert significant impacts on blood pressure and glomerular filtration responses to Ang II remains unknown. In the present study, we tested the hypothesis that deletion of AT1a receptors selectively in the proximal tubules of the kidney attenuates Ang II-induced hypertensive and glomerular filtration responses (GFR) in aging PT-Agtr1a-/- mice. To test the hypothesis, 6 groups (n=8-12 per group) of 20- to 24-month-old male wild-type (WT) and PT-Agtr1a-/- mice were infused with or without a slow pressor dose of Ang II (~0.65 mg/kg/day, i.p.), supplemented with a 2% Na+ diet for 2 weeks. Systolic blood pressure was determined by telemetry and tail-cuff techniques, whereas GFR was measured by the transdermal GFR monitoring technique with FITC-sinistrin, and the pressure-natriuresis responses was determined before and during Ang II infusion, respectively. Basal systolic blood pressure remained significantly lower in aging PT-Agtr1a-/- (104 ± 4 mmHg) than in aging WT mice (120 ± 4 mmHg, P<0.01), whereas basal GFR was significantly higher in aging PT-Agtr1a-/- mice (196.4 ± 14.7 µl/min) than in aging WT mice (142.6 ± 11.6 µl/min, P<0.01). Furthermore, the pressure-natriuresis response was significantly augmented in aging PT-Agtr1a-/-mice (P<0.05). Ang II infusion significantly induced hypertension (152 ± 3 mmHg, P<0.01) and decreased GFR in aging WT mice (122.4 ± 3.3 µl/min, P<0.01), as expected, but the hypertensive (135 ± 3 mmHg, P<0.01) and GFR responses were significantly improved in aging PT-Agtr1a-/-mice (155.9 ± 10.1 µl/min, P<0.01), respectively. Finally, proximal tubule-specific deletion of AT1a receptors significantly augmented the pressure-natriuresis response and natriuretic responses to Ang II infusion in aging PT-Agtr1a-/-mice (P<0.01). Taken together, the results of the present study suggest that intratubular Ang II and AT1a receptors in the proximal tubules continue to play a key role in the development of Ang II-induced hypertension in aging WT mice and that deletion of AT1a receptors selectively in the proximal tubules attenuates Ang II-induced hypertension and improves glomerular filtration in aging PT-Agtr1a-/- mice.