Abstract 41: A Novel Role of the Na+/H+ Exchanger 3 (NHE3) in Angiotensin II-induced Hypertension in Wild-type and NHE3-deficient Mice
The renal mechanisms underlying angiotensin II (ANG II)-induced hypertension remain incompletely understood. We reasoned that the Na+/H+ exchanger 3 (NHE3) in proximal tubules of the kidney may play a key role. In the present study, we used NHE3-deficient mice (Nhe3-/-) to test the hypothesis that NHE3 is required for maintaining long-term blood pressure responses to ANG II. Three groups (n=8 each) of wild-type (Nhe3+/+) and Nhe3-/- mice were treated with vehicle, ANG II (40 ng/min, i.p., via minipump), or ANG II plus losartan (20 mg/kg/day, p.o.) for 2 weeks. Basal and weekly systolic blood pressure (SBP) and urinary water, sodium (Na+), potassium (K+) and chloride (Cl-) excretory responses were measured by the tail-cuff and metabolic cage methods. Under basal conditions, Nhe3-/- mice grew normally (Nhe3+/+: 23±0.3 g vs. Nhe3-/-: 23±0.7 g, n.s.), but had a significantly lower SBP level (Nhe3+/+: 120±3 mmHg vs. Nhe3-/-: 106±3 mmHg, p<0.01), 24 h urine excretion (Nhe3+/+ 1.23±0.15 vs. Nhe3-/-: 0.82±0.10 ml, p<0.05), urinary Na+ excretion (Nhe3+/+: 232.1±10.3 vs. Nhe3-/-: 34.8±3.6 μmol/24 h, p<0.01), and urinary K+ excretion (Nhe3+/+: 343.8±19.4 vs. Nhe3-/-: 194.2±19.8 μmol/24 h, p<0.01). Basal plasma ANG II (Nhe3+/+: 313.4±19.9 vs. Nhe3-/-: 397.7±17.2 pg/ml, p<0.05) and aldosterone levels (Nhe3+/+: 505.6±26.3 vs. Nhe3-/-: 802.8±17.3 pg/ml, p<0.01) were significantly elevated in Nhe3-/- mice. Kidney ANG II levels were not statistically different between Nhe3+/+ and Nhe3-/- mice. In Nhe3+/+ mice, ANG II infusion markedly increased SBP in a time-dependent manner (p<0.01). However, the SBP response to ANG II was markedly attenuated in Nhe3-/- mice despite plasma ANG II and aldosterone levels were further elevated by ANG II infusion (Nhe3+/+: 165±4 mmHg vs. Nhe3-/-: 119±4 mmHg, p<0.01 at 2 weeks). 24 h urinary K+ and Cl- excretory responses were increased by ANG II in Nhe3-/- mice without altering 24 h urinary Na+ excretion. Concurrent losartan treatment normalized SBP responses to ANG II in Nhe3+/+ mice, but markedly increased the mortality in Nhe3-/- mice. We concluded that NHE3 in proximal tubules of the kidney, along with NHE3 in intestines, is required for maintaining long-term blood pressure responses to ANG II and body salt and fluid homeostasis in mice.
- © 2012 by American Heart Association, Inc.