We have recently shown that angiotensin (ANG II)-induced hypertension was attenuated in mice with global (
Nhe3
-/-
) and
Nhe3
-/-
mice with transgenic rescue of the NHE3 gene selectively in small intestines (tg
Nhe3
-/-
), suggesting an important role of NHE3 in the development of ANG II-dependent hypertension. In this study, we specifically tested whether the pharmacological inhibition of NHE3 mainly in the proximal tubules of the kidney attenuates ANG II-dependent hypertension induced by a low and slow pressor dose of ANG II supplemented with a high salt diet. Overall, 9 groups (n=5-12) of adult male C57BL/6J mice were infused with or without ANG II (500 μg/kg/day, i.p. via minipump) and supplemented with or without a 2% NaCl diet to slowly and moderately increase systolic blood pressure (SBP) in 2 weeks. ANG II alone increased SBP from 116 ± 2 mmHg to 140 ± 2 mmHg (
p
<0.01), and supplement of ANG II with a 2% NaCl diet further increased SBP to 147 ± 4 mmHg (
p
<0.05). Concurrent treatment with an orally active, absorbable NHE3 inhibitor AVE0657 (Sanofi-Aventis; 20 mg/kg/day, p.o.) significantly decreased SBP to 125 ± 4 mmHg in ANG II-infused mice (
p
<0.01), and to 134 ± 6 mmHg in ANG II-infused mice supplemented with 2% NaCl (
p
<0.01), respectively. Further treatment with AVE0657 and losartan, an AT
1
receptor blocker (20 mg/kg/day, p.o.), completely normalize SBP in mice treated with ANG II and 2% NaCl to control (115 ± 5 mmHg,
p
<0.01). In the kidney, AVE0657 significantly increased 24h urinary Na
+
excretion from 157.1 ± 6.7 to 207.7 ± 8.1 μmol/24h (
p
<0.01) without altering 24h urine excretion or SBP. Furthermore, AVE0657 did not significantly alter 24 h fecal Na
+
excretion in non ANG II-infused (4.99 ± 0.37 μmol/24h, n.s.) or ANG II-infused mice (4.19 ± 0.67 μmol/24h, n.s.), compared with control (4.02 ± 0.20 μmol/24h,
n.s.
) or global
Nhe3
-/-
mice (50.8 ± 0.8 μmol/24h,
p
<0.01). Since small intestines in the gut and the proximal tubules of the kidney express the vast majority of NHE3 in the body, these results provide preclinical evidence and perspectives that orally absorbable NHE3 inhibitors may be pharmacologically beneficial to prevent and treat hypertension induced by ANG II and a high salt, mainly by inhibiting NHE3 in the proximal tubule of the kidney.
A Novel Missense Mutation in AE1 Causing Autosomal Dominant Distal Renal Tubular Acidosis Retains Normal Transport Function but Is Mistargeted in Polarized Epithelial Cells