The Deletion of AT1a Receptors Selectively in The Proximal Tubules of The Kidney Lowers Blood Pressure by Inducing Glomerular Hyperfiltration and Pressure‐Natriuresis Responses in PT‐Agtr1a−/− Mice
Authors: Li Xiao Chun , De Oliveira Leite Ana Paula , Zheng Xiaowen , Zhao Chunling , Zhu Dongmin , Zhuo Jia Long 
Published: April 2020

The renin‐angiotensin system (RAS) in the proximal tubules of the kidney plays a key role in the physiological regulation of proximal tubular Na+ reabsorption and normal blood pressure homeostasis. Inappropriate activation of intratubular RAS in the proximal tubules may contribute to angiotensin II (Ang II)‐induced hypertension. In the present study, we used proximal tubule‐specific knockout of AT1a receptors (PT‐Agtr1a−/−) in the kidney to test the hypothesis that Ang II and AT1a receptors in the proximal tubules are required for normal blood pressure homeostasis and full development of Ang II‐induced hypertension by altering glomerular filtration and the pressure‐natriuresis responses. To test the hypothesis, six groups (n=7–12 per group) of adult male wild‐type (WT) and PT‐Agtr1a−/− mice were infused with or without Ang II via osmotic minipump for 2 weeks (1.5 mg/kg, i.p.). Glomerular filtration rate (GFR) was monitored by an intradermal device using fluorescein‐labeled sinistrin, and natriuretic responses were determined under basal conditions and after Ang II infusion for 2 weeks. Basal systolic blood pressure were ~13 ± 3 mmHg lower in PT‐Agtr1a−/− than WT mice (P<0.01). However, basal GFR was significantly higher in PT‐Agtr1a−/− mice (WT: 160.4 ± 7.0 μl/min vs. PT‐Agtr1a−/−: 186.0 ± 10 μl/min, P<0.01). Basal 24 h urinary Na+ excretion (UNaV) was significantly higher in PT‐Agtr1a−/− than WT mice (P<0.01). In response to Ang II infusion, both WT and PT‐Agtr1a−/− mice developed hypertension, and the magnitude of the pressor response to Ang II was similar in WT (Δ43 ± 3 mmHg, P<0.01) and PT‐Agtr1a−/− mice (Δ39 ± 5 mmHg, P<0.01). However, the absolute systolic blood pressure level was still 16 ± 3 mmHg lower in PT‐Agtr1a−/− mice (P<0.01). Ang II significantly decreased GFR to 132.2 ± 7.0 μl/min in WT mice (P<0.01), and to 129.4 ± 18.6 μl/min in PT‐Agtr1a−/− mice (P<0.01), respectively. In WT mice, UNaV increased from 139.3 ± 22.3 μmol/24 h in the control group to 196.4 ± 29.6 μmol/24 h in the Ang II‐infused group (P<0.01). In PT‐Agtr1a−/− mice, UNaV increased from 172.0 ± 10.2 μmol/24 h in the control group to 264.7 ± 35.4 μmol/24 h in the Ang II‐infused group (P<0.01). The pressor response to Ang II was attenuated, while the natriuretic response was augmented by losartan in WT and PT‐Agtr1a−/− mice (P<0.01). Finally, proximal tubule‐specific deletion of AT1a receptors significantly augmented the pressure‐natriuresis response and natriuretic responses to acute saline infusion (P<0.01) or a 2% high salt diet for 2 weeks (P<0.01). In conclusion, the present study supports the hypothesis that Ang II and AT1a receptors in the proximal tubules are required for normal blood pressure homeostasis and the full development of Ang II‐induced hypertension, and suggest that deletion of AT1a receptors selectively in the proximal tubules lowers basal blood pressure by inducing glomerular hyperfiltration and promoting the natriuretic response in PT‐Agtr1a−/− mice.

Support or Funding Information

This work was supported in part by NIDDK grants, 2R01DK067299‐06A2, 2R01DK067299‐10A1, 5R01DK102429‐01, and 2R01DK102429‐03A1 to Dr. Zhuo.