Abstract P111: Deletion Of Na + /H + Exchanger 3 Selectively In The Proximal Tubules Doesn’T Prevent The Development Of Doca-salt Hypertension In Pt- Nhe3 -/- Mice

Abstract

We have previously shown that genetic deletion of Na + /H + exchanger 3 (NHE3) selectively in the proximal tubules lowered basal blood pressure and attenuated the development of angiotensin II (Ang II)-induced hypertension by promoting the pressure-natriuresis response. However, it is not known whether deletion of the NHE3 gene selectively in the proximal tubules attenuates salt-sensitive hypertension induced by DOCA-Salt. In the present study, we tested the hypothesis that the development of DOCA-Salt hypertension is attenuated by genetic deletion of NHE3 selectively in the proximal tubules of the kidney. To test the hypothesis, mice with proximal tubule-specific deletion of NHE3, i.e., PT- Nhe3 -/- , were generated using the iL- Sglt2-Cre / Nhe3 flox approach. Adult male PT- Nhe3 -/- mice were treated with or without DOCA (10 mg/10 g body wt., subcutaneously), supplemented with 2% high salt diet, for 4 weeks. Basal and weekly systolic (SBP), diastolic (DBP), and mean arterial pressure (MAP) were determined using the indirect tail-cuff method, whereas 24 hr. urinary sodium, potassium, and chloride excretion were determined using a metabolic cage. Compared with the time-control group (n=12), treatment with DOCA-salt moderately but significantly increased systolic SBP from 96 ± 3 mmHg to 126 ± 5 mmHg in PT- Nhe3 -/- mice (n=8; P <0.01). DBP and MAP increased to similar extents in response to DOCA-salt treatment ( P <0.05). As expected, DOCA-salt hypertension significantly increased the pressure-natriuresis response, i.e., 24 hr. urinary sodium excretion by 55% (Control: 152 ± 19 vs. DOCA-Salt: 236 ± 2 μmol/24 hr; P <0.01), potassium excretion by 52% (Control: 147 ± 16 vs. DOCA-Salt: 224 ± 18 μmol/24 hr; P <0.01), and chloride excretion by 71% (Control: 181 ± 27 vs. DOCA-Salt: 310 ± 31 μmol/24 hr; P <0.01), respectively. Taken together, these data do not support our hypothesis and suggest that deletion of NHE3 selectively in the proximal tubules doesn’t prevent the development of DOCA-Salt hypertension in PT- Nhe3 -/- mice.