Abstract P2016: Proximal Tubule-Specific Knockout of Angiotensin II Type 1a Receptors in the Kidney Augments the Natriuretic Response to Angiotensin III in Mice

Abstract

Angiotensin III (ANG III), a major metabolite of the potent vasopressor hormone ANG II, reportedly binds and activates AT 2 receptors to oppose the AT 1 receptor-mediated antinatriuretic effect of ANG II in the proximal tubules of the kidney. The present study tested the hypothesis that global ( Agtr1a -/- ) or proximal tubule-specific deletion of AT 1a receptors in the kidney (PT- Agtr1a -/- ) attenuates the blood pressure, but augments renal Na + excretory responses to ANG III in mice. Proximal tubule AT 1a receptor knockout mice (PT- Agtr1a -/- ) were generated using the Sglt2-Cre/ Agtr1a -floxed approach. Adult male wild-type littlemates (WT), global ( Agtr1a -/- ), and PT- Agtr1a -/- mice (n =7-10 for each group) were anesthetized and infused with saline or increasing doses of ANG III, at 10, 50, and 100 ng/min, i.v ., respectively, for 60 min each. An additional group of PT- Agtr1a -/- mice (n=7) was infused with ANG III at 1.5 mg/kg/day, i.p ., via osmotic minipump for 2 weeks. Basal systolic, diastolic, and mean arterial blood pressure were significantly lower ( p <0.01), whereas 24 h urinary Na + excretion was significantly higher in Agtr1a -/- and PT- Agtr1a -/- than WT mice ( p <0.01). ANG III significantly increased systolic blood pressure from 82 ± 5 mmHg to 116 ± 8 mmHg in anesthetized WT mice (n=8, p <0.01 vs. baseline), and from 75 ± 3 mmHg to 109 ± 6 mmHg in anesthetized PT- Agtr1a -/- mice (n=10, p <0.01 vs. baseline). There was no significant difference in the net pressor response to ANG III between WT and PT- Agtr1a -/- mice. A similar pressor effect to ANG III was confirmed in conscious PT- Agtr1a -/- mice (Basal: 97 ± 2 mmHg vs. ANG III: 111 ± 5 mmHg, n=7, p <0.05). Global deletion of AT 1a receptors completely blocked the pressor effect of ANG III in Agtr1a -/- mice (n=7, p <0.05 vs. WT or PT- Agtr1a -/- mice). In WT mice, ANG III induced small, but significant, antinatriuretic responses at 10 and 50 ng/min ( p <0.05), respectively. Conversely, ANG III induced small, but significant, natriuretic responses at 50 and 100 ng/min in PT- Agtr1a -/- mice ( p <0.05). These results suggest that the pressor effect of ANG III is mediated by systemic AT 1a receptors, whereas the natriuretic effect of ANG III in PT- Agtr1a -/- mice may involve AT 2 receptors in the proximal tubules of the kidney.