Abstract
Objectives: The Na+/H+ exchanger 3 (NHE3) plays an important role in the regulation of blood pressure and the pathogenesis of hypertension. The present study tested the hypothesis that genetic deletion of NHE3 selectively in the proximal tubule of the kidney prevents L-NAME-induced hypertension in mice. Methods: To test the hypothesis, adult male and female C57BL/6J mice (WT) and mice with proximal tubule-specific knockout of NHE3 (PT-NHE3-KO) were treated with the nitric oxide synthase inhibitor L-NAME (50 mg/kg/day, p.o.) for 4 weeks. Systolic blood pressure (SBP), 24 h urinary sodium excretion, and renal transporter proteins were determined before and weekly after L-NAME treatment. The results were analyzed using one-way ANOVA or unpaired t test, as appropriate. Results: Basal SBP was significantly lower in both male and female PT-NHE3-KO mice than WT male (WT: 118 ± 3 mmHg, n = 9 vs. PT-NHE3-KO: 109 ± 2, n = 12, p < 0.01) and female mice (WT: 116 ± 5 mmHg, n = 10 vs. PT-NHE3-KO: 105 ± 3, n = 15, p < 0.01). No differences in basal SBP were found between male and female WT or PT-NHE3-KO mice. L-NAME treatment caused time-related increases in SBP, which peaked at 2 weeks and sustained for 4 weeks in both WT (Male: 126 ± 5 mmHg, n = 5 vs. Female: 124 ± 3, n = 5; p < 0.01 vs. basal) and PT-NHE3-KO mice (Male: 118 ± 3 mmHg, n = 12 vs. Female: 115 ± 3, n = 15; p < 0.01 vs. basal). L-NAME-induced hypertension was associated with antinatriuresis in WT mice (p < 0.05 vs. basal), but it was conversely associated with natriuresis in female PT-NHE3-KO mice (p < 0.01 vs. basal). Conclusion: The results of the present study do not support the hypothesis that NHE3 in the proximal tubule of the kidney plays a key role in the development of L-NAME-induced hypertension (supported by 2R01DK102429–03A1, 2R01DK067299-10A1, and 1R56HL130988 to Zhuo).
Published Version
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