A key role of AT1a 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 AT1a 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 AT1a receptor and NHE3 double knockout mice, PT-Agtr1a-/-/Nhe3-/-, were generated using the iL-Sglt2-Cre/LoxP approach. Male and female wild-type (WT) and PT-Agtr1a-/-/Nhe3-/- 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 (n = 9), which increased to 161 ± 3 mmHg in response to Ang II infusion (P < 0.01, n = 10) or to 136 ± 3 mmHg in response to induction of 2K1C Goldblatt hypertension (n = 12, P < 0.01). By comparison, basal SBP was 13 ± 2 mmHg lower in PT-Agtr1a-/- (P < 0.01) or in PT-Nhe3-/- single-gene knockout mice than WT mice (P < 0.01). Double deletion of AT1a and NHE3 in the proximal tubules further lowered basal SBP by 6 ± 2 mmHg in PT-Agtr1a-/-/Nhe3-/- mice (P < 0.05). In response to Ang II infusion, SBP increased to 121 ± 3 mmHg in PT-Agtr1a-/-/PT-Nhe3-/- mice (P < 0.01). 2K1C Goldblatt hypertension was attenuated in PT-Agtr1a-/- (108 ± 3 mmHg, P < 0.01, n = 10), PT-Nhe3-/- (110 ± 2 mmHg, P < 0.01, n = 10), or PT-Agtr1a-/-/Nhe3-/- mice (103 ± 2 mmHg, P < 0.01, n = 8), respectively. Taken together, our study provides further evidence for a key role of proximal tubule AT1a receptors and NHE3 in the development of Ang II-induced and 2K1C Goldblatt hypertension.NEW & NOTEWORTHY This study generates a novel mouse model with double deletion of AT1a 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 AT1a receptor and NHE3 not only in maintaining physiological blood pressure homeostasis but also in the development of Ang II-induced and 2K1C Goldblatt hypertension.