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 AT 1a receptors and 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- 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 weeks (1.5 mg/kg body wt./day, i.p.) or induced with 2K1C Goldblatt hypertension for 4 weeks. In 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 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 AT 1a 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 AT 1a receptors and NHE3 in the development of Ang II-induced and 2K1C Goldblatt hypertension.