Abstract P167: Conditional Deletion of the Na+/H+ Exchanger 3 in the Proximal Tubule of the Kidney Promotes Pressure Natriuresis in Mice
The development and progression of most, if not all, forms of hypertension appear to converge on a final common pathway or mechanism, i.e., increased renal salt retention due to significantly impaired pressure natriuresis responses. Yet the factors responsible for resetting the pressure natriuresis response in hypertension remain to be determined. The present study tested the hypothesis that the upregulation of the sodium and hydrogen exchanger 3 (NHE3) impairs while selective knockout of this transporter in the proximal tubule promotes pressure natriuresis and lowers blood pressure in mice. Proximal tubule-specific NHE3 knockout mice (PT-NHE3-KO) were generated by the Cre/Lox approach, and confirmed by complementary PCR, Western blot, and immunofluorescent imaging of NHE3 expression in the proximal tubule of the kidney, respectively. No abnormal histological phenotypes were observed in small intestines and the kidney of PT-NHE3-KO mice. Compared with wild-type mice (WT, n=12), PT-NHE3-KO mice (n=10) had significantly lower basal systolic blood pressure (WT: 116 ± 3 mmHg versus PT-NHE3-KO: 103 ± 3 mmHg, p<0.01). Mean intra-arterial pressure was also significantly lower in anesthetized PT-NHE3-KO mice (WT: 91 ± 3 mmHg versus PT-NHE3-KO: 77 ± 5 mmHg, p<0.01) (n=8 each). The lower basal blood pressure in PT-NHE3-KO mice was associated with higher basal urine flow (WT: 0.81 ± 0.09 ml/day versus PT-NHE3-KO: 1.12 ± 0.06 ml/day, p<0.05), urinary sodium (WT: 120.1 ± 17.5 μmol/day versus PT-NHE3-KO: 197.1 ± 24.5 μmol/day, p<0.01), potassium (WT: 171.7 ± 26.0 μmol/day versus PT-NHE3-KO: 310.3 ± 24.3 μmol/day, p<0.01), and chloride excretion (WT: 125.7 ± 22.5 μmol/day versus PT-NHE3-KO: 222 ± 29.2 μmol/day, p<0.05) (n=8-12 for each group). In response to ~25 mmHg increase in renal perfusion pressure in both strains, urinary sodium excretion was increased by 4-fold in WT mice (n=12, p<0.01), whereas it increased by 7-fold in PT-NHE3-KO mice (n=10, p<0.01). We concluded that NHE3 in the proximal tubule of the kidney plays an important role in the regulation of proximal tubular sodium reabsorption and blood pressure homeostasis, and that selective deletion of NHE3 in the proximal tubule promotes the pressure natriurestic response and lowers blood pressure in mice.
Author Disclosures: X.C. Li: None. M. Soleimani: None. H. Nguyen: None. H. Li: None. R.J. Roman: None. J.L. Zhuo: None.
- © 2015 by American Heart Association, Inc.