Role of the Na + /H + exchanger 3 in angiotensin II ‐induced hypertension in NHE 3‐deficient mice with transgenic rescue of NHE 3 in small intestines

Abstract The role of Na +/ H + exchanger 3 ( NHE 3) in the kidney in angiotensin II ( ANG II )‐induced hypertension remains unknown. The present study used global NHE 3‐deficient mice with transgenic rescue of the Nhe3 gene in small intestines (tg Nhe3 −/− ) to test the hypothesis that genetic deletion of NHE 3 selectively in the kidney attenuates ANG II ‐induced hypertension. Six groups of wild‐type (tg Nhe3 +/+ ) and tg Nhe3 −/− mice were infused with either vehicle or ANG II (1.5 mg/kg/day, i.p., 2 weeks, or 10 nmol/min, i.v., 30 min), treated with or without losartan (20 mg/kg/day, p.o.) for 2 weeks. Basal systolic blood pressure ( SBP ) and mean intra‐arterial blood pressure ( MAP ) were significantly lower in tg Nhe3 −/− mice ( P  <   0.01). Basal glomerular filtration rate, 24 h urine excretion, urinary Na + excretion, urinary K + excretion, and urinary Cl − excretion were significantly lower in tg Nhe3 −/− mice ( P  <   0.01). These responses were associated with significantly elevated plasma ANG II and aldosterone levels, and marked upregulation in aquaporin 1, the Na + / HCO 3 cotransporter, the α 1 subunit isoform of Na + /K + ‐ ATP ase, protein kinase C α , MAP kinases ERK 1/2, and glycogen synthase kinase 3 α / β in the renal cortex of tg Nhe3 −/− mice ( P  <   0.01). ANG II infusion markedly increased SBP and MAP and renal cortical transporter and signaling proteins in tg Nhe3 +/+ , as expected, but all of these responses to ANG II were attenuated in tg Nhe3 −/− mice ( P  <   0.01). These results suggest that NHE 3 in the kidney is necessary for maintaining normal blood pressure and fully developing ANG II ‐dependent hypertension.