The Deletion of NHE3 Selectively in The Proximal Tubules Does not Alter the Blood Pressure Response to Angiotensin III in Male and Female Proximal Tubule‐Specific NHE3 Knockout Mice

Abstract

ObjectivesWe have recently shown that the pressor and renal Na+ excretory responses to angiotensin II (ANG II) were significantly attenuated in global (Nhe3−/−), kidney‐selective (tgNhe3−/−), and proximal tubule‐specific NHE3 knockout mice (PT‐Nhe3−/−). The present study tested the hypothesis that deletion of NHE3 selectively in the proximal tubules of the kidney alters the blood pressure and renal Na+ responses to its major metabolite, ANG III, which reportedly binds and activates AT2 receptors and inhibits NHE3 in the proximal tubules.MethodsProximal tubule NHE3 knockout mice (PT‐Nhe3−/−) were generated using the sglt2‐Cre/NHE3‐floxed approach. To test the hypothesis, adult and age‐matched male and female wild‐type littlemates (WT) and PT‐Nhe3−/− mice (n = 10–11 each group) were infused with or without ANG III at 1.5 mg/kg/day via osmotic minipump, i.p., for 2 weeks. Systolic, diastolic and mean arterial blood pressure, and 24 h urinary Na+ excretory responses were determined before and weekly after treatment.ResultsUnlike global Nhe3−/− mice, no abnormal intestinal structural and absorptive dysfunction was found in proximal tubule‐specific NHE3 knockout mice (PT‐Nhe3−/−). At 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 male PT‐Nhe3−/− than male WT mice (p<0.01). ANG III significantly increased systolic blood pressure from 113 ± 2 mmHg to 127 ± 3 mmHg in WT mice (n=10, p<0.01 vs. baseline), and from 104 ± 3 mmHg to 116 ± 5 mmHg in PT‐Nhe3−/− mice (n=11, p<0.01 vs. baseline). However, there were no differences in the net pressor and heart rate responses to ANG III between male and female WT and PT‐Nhe3−/− mice. ANG III also significantly increased 24 h urinary Na+ excretion in male WT mice (n=10, p<0.05 vs. baseline), but not in male PT‐Nhe3−/− mice (n=11, n.s.). There were no significant differences in 24 h urinary Na+ excretion between female WT (n=10, n.s.) and PT‐Nhe3−/− mice (n=10, n.s.). Finally, ANG III infusion did not significantly alter the heart‐ or kidney‐to‐body wt. ratio, blood volume, or hematocrit in male and female WT and PT‐Nhe3−/− mice, respectively.ConclusionThe deletion of NHE3 selectively in the proximal tubules of the kidney doesn't significantly alter the blood pressure responses to ANG III in male and female PT‐Nhe3−/− mice, but it does attenuate the natriuretic response to ANG III in male PT‐Nhe3−/− mice.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.