A key role of AT_1a receptors and Na⁺/H⁺ exchanger 3 in the proximal tubules in angiotensin II-induced and two-kidney, one-clip Goldblatt hypertension

The present study tests the hypothesis that dual deletion of AT_1a receptors and Na⁺/H⁺ exchanger 3 (NHE3) selectively in the proximal tubules further attenuates angiotensin II (Ang II)-induced and two-kidney, one-clip (2K1C) Goldblatt hypertension. Proximal tubule (PT)-specific AT_1a receptor and NHE3 double knockout mice, PT-<i>Agtr1a^-</i>^/<i>^-</i>/<i>Nhe3^-</i>^/<i>^-</i>, were generated using the iL-<i>Sglt2-Cre</i>/<i>LoxP</i> approach. Male and female wild-type (WT) and PT-<i>Agtr1a^-</i>^/<i>^-</i>/<i>Nhe3^-</i>^/<i>^-</i> double knockout mice were infused with a pressor dose of Ang II for 2 wk (1.5 mg/kg body wt/day ip) or induced with 2K1C Goldblatt hypertension for 4 wk. In wild-type (WT) mice, basal systolic blood pressure (SBP) was 118 ± 3 mmHg (<i>n</i> = 9), which increased to 161 ± 3 mmHg in response to Ang II infusion (<i>P</i> < 0.01, <i>n</i> = 10) or to 136 ± 3 mmHg in response to induction of 2K1C Goldblatt hypertension (<i>n</i> = 12, <i>P</i> < 0.01). By comparison, basal SBP was 13 ± 2 mmHg lower in PT-<i>Agtr1a^-</i>^/<i>^-</i> (<i>P</i> < 0.01) or in PT-<i>Nhe3^-</i>^/<i>^-</i> single-gene knockout mice than WT mice (<i>P</i> < 0.01). Double deletion of AT_1a and NHE3 in the proximal tubules further lowered basal SBP by 6 ± 2 mmHg in PT-<i>Agtr1a^-</i>^/<i>^-</i>/<i>Nhe3^-</i>^/<i>^-</i> mice (<i>P</i> < 0.05). In response to Ang II infusion, SBP increased to 121 ± 3 mmHg in PT-<i>Agtr1a^-</i>^/<i>^-</i>/PT-<i>Nhe3^-</i>^/<i>^-</i> mice (<i>P</i> < 0.01). 2K1C Goldblatt hypertension was attenuated in PT-<i>Agtr1a^-</i>^/<i>^-</i> (108 ± 3 mmHg, <i>P</i> < 0.01, <i>n</i> = 10), PT-<i>Nhe3^-</i>^/<i>^-</i> (110 ± 2 mmHg, <i>P</i> < 0.01, <i>n</i> = 10), or PT-<i>Agtr1a^-</i>^/<i>^-</i>/<i>Nhe3^-</i>^/<i>^-</i> mice (103 ± 2 mmHg, <i>P</i> < 0.01, <i>n</i> = 8), respectively. Taken together, our study provides further evidence for a key role of proximal tubule AT_1a receptors and NHE3 in the development of Ang II-induced and 2K1C Goldblatt hypertension.<b>NEW & NOTEWORTHY</b> This study generates a novel mouse model with double deletion of AT_1a receptors and Na⁺/H⁺ exchanger 3 (NHE3) in the proximal tubules to directly determine their role in the development of Ang II-induced and two-kidney, one-clip (2K1C) Goldblatt hypertension. This study provides further evidence for a key role of proximal tubule AT_1a receptor and NHE3 not only in maintaining physiological blood pressure homeostasis but also in the development of Ang II-induced and 2K1C Goldblatt hypertension.