GENETIC DELETION OR PHARMACOLOGICAL INHIBITION OF THE SODIUM AND HYDROGEN EXCHANGER 3 IN THE PROXIMAL TUBULES OF THE KIDNEY ATTENUATES ANGIOTENSIN II AND SALT-INDUCED HYPERTENSION

Abstract

Objective: According to American Heart Association, ∼46% of American adults have hypertension and ∼13 of these patients develop poorly controlled hypertension even treated with >3 - 4 different classes of antihypertensive drugs. The mechanisms underlying poorly controlled hypertension remain incompletely understood. The present study tested the proof of concept hypothesis that the sodium and hydrogen exchanger 3 (NHE3) in the proximal tubules of the kidney may be a therapeutic target of angiotensin II (Ang II) and salt-induced hypertension in mice. Design and method: To test the hypothesis, we generated a new mouse model with deletion of NHE3 selectively in the proximal tubules of the kidney using the iL-Sglt2-Cre and Nhe3-floxed approach (PT-Nhe3-/-). Adult male wildtype (WT) and PT-Nhe3-/- mice were infused without or with a low dose of Ang II (0.5 mg/kg/day, i.p., via minipump) and maintained on 2% high salt diet for 2 weeks to induce Ang II- and salt-dependent hypertension. Animals were then treated without or with an absorbable NHE3 inhibitor AVE-0657 for 2 weeks (20 mg/kg/day, p.o., a gift of Sanofi-Aventis). Results: Under basal conditions, deletion of NHE3 selectively in the proximal tubules of the kidney decreased basal systolic and mean blood pressure by ∼13 ± 3 mmHg in PT-Nhe3-/- mice (P < 0.01 vs. WT), whereas inhibition of NHE3 primarily in the proximal tubules with AVE-0657 lowered basal blood pressure by ∼7 ± 2 mmHg in WT mice (P < 0.05 vs. control WT). Ang II and high salt treatment significantly increased blood pressure by 26 ± 5 mmHg in WT mice (P < 0.01), which was significantly attenuated in PT-Nhe3-/- mice (P < 0.01). Ang II and salt-induced hypertension in WT mice was also significantly attenuated by NHE3 inhibition in the kidney proximal tubules with AVE-0657 (P < 0.01). Concurrent treatment with losartan, an AT1 receptor blocker (20 mg/kg/day, p.o.), completely lowered blood pressure to control level in WT mice (P < 0.05). AVE-0657 had no further effect on blood pressure in PT-Nhe3-/- mice. Conclusions: In conclusion, our results support the proof of concept hypothesis that NHE3 in the proximal tubules of the kidney may be a therapeutic target of Ang II and salt-induced hypertension.