The Deletion of AT1a Receptors Selectively in The Proximal Tubules of The Kidney Augments The Natriuretic Response to Angiotensin III in PT‐Agtr1a−/− Mice

Abstract

ObjectiveAngiotensin III (ANG III) is a major metabolite of the potent vasopressor hormone ANG II, and it reportedly binds and activates AT2 receptors to counteract the AT1 receptor‐mediated antinatriuretic effect of ANG II in the proximal tubules of the kidney. Whether global or proximal tubule‐specific deletion of AT1a receptors alters the blood pressure and renal effects of ANG III has not be investigated previously. The present study was designed to test the hypothesis that deletion of AT1a receptors globally or selectively in the proximal tubules of the kidney attenuates the blood pressure and renal Na+ excretory responses to ANG III in mice.MethodsTo test the hypothesis, proximal tubule AT1a receptor knockout mice (PT‐Agtr1a−/−) were generated using the sglt2‐Cre/Agtr1a‐floxed approach. Adult and age‐matched male wild‐type littlemates (WT), global (Agtr1a−/−), and PT‐Agtr1a−/− mice (n =4–7 for each group) were anesthetized and infused with saline or increasing doses of the major ANG II metabolite, ANG III, at 10, 50, and 100 ng/min, i.v., for 60 min each. An additional group of PT‐Agtr1a−/− mice (n=7) was infused with ANG III at 40 ng/min, i.p., via osmotic minipump for 2 weeks. Systolic, diastolic and mean arterial blood pressure and urinary Na+ excretory responses were determined before and after ANG III infusion.ResultsAt the basal level, systolic, diastolic, and mean arterial blood pressure was significantly lower (p<0.01), whereas 24 h urine and urinary Na+ excretion were significantly higher in conscious male Agtr1a−/− and PT‐Agtr1a−/− than WT mice (p<0.01). Compared with control, ANG III significantly increased systolic blood pressure from 82 ± 5 mmHg to 116 ± 8 mmHg in WT mice (n=6, p<0.01 vs. baseline), and from 75 ± 3 mmHg to 109 ± 6 mmHg in PT‐Agtr1a−/− mice (n=7, p<0.01 vs. baseline). However, there was no difference in the net pressor response to ANG III between WT and PT‐Agtr1a−/− mice. A similar pressor effect of ANG III was also confirmed in conscious PT‐Agtr1a−/− mice infused with ANG III at 40 ng/min, i.p., for 2 weeks (Basal: 97 ± 2 mmHg vs. ANG III: 111 ± 5 mmHg, n=7, p<0.05). Global deletion of AT1a receptors completely blocked the pressor effect of ANG III in Agtr1a−/− mice (n=4, 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).ConclusionThe deletion of AT1a receptors selectively in the proximal tubules of the kidney doesn't significantly alter the blood pressure responses to ANG III, but it does moderately augment the natriuretic response to ANG III in PT‐Agtr1a−/− mice. These results suggest that the pressor effect of ANG III is mediated by AT1a receptors, whereas the natriuretic effect of ANG III in PT‐Agtr1a−/− mice may involve AT2 receptors in the proximal tubules of the kidney.Support or Funding InformationThis work was supported in part by NIH grants, 2R01DK102429‐03A1, 2R01DK067299‐10A1, and 1R56HL130988‐01 to Dr. Jia Zhuo.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.